U. S. DEPARTMENT OF AGRICULTURE, 
BUREAU OF CHEMISTffY— BULLETIN NO. 80. 



H W WILEY Chief o 



i Bui eau 



ADULTERATED DRUGS AXD CHEMICALS; 



I. Inferior Ornsrs and Insidious Methods of Deception. 
II. Rose Geranium Oil and Its Substitutes. 
[II. Plieuaoetiii: Methods of Analysis and Commercial Static 



By LYAIAX V. KEBLER, 
Chief of Drug laboratory. 




WASHINGTON: 

t? OVRK N M E X T PRIXTIM; O F F I < " E 
19 4. 



U. S. DEPARTMENT OF AGRICULTURE, 

n 

BUREAU OF CHEMISTRY— BULLETIN NO. 80. 

H. W. WILEY, Chief of Bureau. 




ADULTERATED DRUGS AND CHEMICALS. 



I. Inferior Drugs and Insidious Methods of Deception. 
II. Rose Geranium Oil and Its Substitutes. 
III. Phenacetin: Methods of Analysis and Commercial Status. 



By LYMAN T\ KEBLER, 

Chief of Drug Laboratory. 




WASHINGTON: 

GOVERNMENT PRINTING OFFICE. 

1904. 



r 






LETTER OF TRANSMITTAL. 



l'. S. Department op Agriculture, 

Bureau of Chemistry, 
Waxhiiujton, D. C. November 6, 1903. 
Sib: I have the honor to transmit for your inspection and approval 
a manuscript reporting the results of investigations relative to the 
adulteration of certain drugs and chemicals. These investigations 
were carried <>n chiefly in the drug laboratory of this Bureau, although 
some of the \\<»rk described was done by Mr. Kebler before taking 
charge <>l' that laboratory. I recommend that this manuscript be 
published as Bulletin No. 80 of this Bureau. 
Respectfully, 

II. W. Wiley, Chief. 
Hon. James Wilson, 

Seen tary of . Igriadtun . 



^ 



INTRODUCTION. 



The first two articles of this bulletin set forth the conditions that 
prevail not only in relation to individuals, but also in some of the best- 
regulated laboratories. There is a continual cry for cheaper drugs, 
and in the effort to meet this demand and at the same time make a 
profit adulteration has spread. The members of the pharmaceutical 
profession of high standing, however, are anxious to remove from the 
trade any odium due to adulteration which at present exists. 

The third paper deals with the patented medicinal remedy phenacetin, 
which according to reports has been largely adulterated in this country 
and manjr substitutes offered therefor. This subject was studied 
because of the great interest that exists concerning it in both the 
medical and the pharmaceutical world, many druggists and physicians 
being directly involved in the controversy. The fact that phenacetin 
is sold for 15 cents an ounce in Canada, while $1 or more is charged 
for the same amount in the United States, creates an impression, cor- 
rect or incorrect, of injustice. The conditions set forth concerning 
phenacetin are, moreover, typical of those affecting a large number of 
patented medicinal remedies. Furthermore, the attempts that have 
been made to secure such changes in the patent laws as would elimi- 
nate these disturbing factors have not been successful. It is hoped 
that the contents of this paper will place the whole situation before 
the public in a just and impartial manner. 

H. W. Wiley, 

Chief of Bureau. 
3 



CONTENTS. 



I. — Infekiok Drugs and Insidious Methods of Deception 7 

Introduction 7 

Conventional adulterations 8 

Bleached ginger 9 

Cochineal 10 

Availability of the pure product 10 

Methods of analysis 10 

Accidental adulterations 12 

Deteriorated drugs 13 

"C. P." chemicals 14 

Adulterations resulting from arbitrary standards 16 

Analyses of certain oils and potassium cyanids 17 

Methods of estimating chlorids in soluble cyanids 18 

Intentional adulterations . 19 

Siftings and sweepings 20 

A common method of deception : 21 

II. — Rose Geranium Oil and its Substitutes 23 

III. — Phenacetin: Methods op Analysis and Commercial Status 27 

Historical review 27 

Phenacetin patents and trade-marks 33 

Methods of manufacture 37 

Physical and chemical tests 38 

The melting point 38 

Solubility 40 

Chemical tests for acetanilid in phenacetin 40 

Bromin test 40 

Saponification test 41 

Mercurous nitrate test 42 

Iodophenol test 42 

Isonitril reaction 42 

Conflicting statements regarding the isonitril reaction . 43 

Commercial samples 44 

Various labels 44 

Analytical results 45 

Commerce in phenacetin 46 

5 



ADULTERATED DRUGS AND CHEMICALS. 



I.— INFERIOR DRUGS AND INSIDIOUS METHODS OF 
DECEPTION. 

INTRODUCTION. 

The adulteration of medicinal remedies is brought to our attention 
from time to time, and it will probably not be denied by many that 
the basic facts as given to the public are, in the main, correct; but 
f requentty the worst possible interpretation is given them. There are, 
undoubtedly, members of the pharmaceutical profession whose sense 
of honor is so distorted by rapacity and greed that they unconsciously, 
if not deliberately, drift into mendaciousness. These are the men 
who usualty bring the craft into ill repute. Some of the excuses 
given by these dealers, when informed concerning the shortcomings 
of their goods, are both interesting and instructive. For example, 
they contend that it would not be safe to suppty their customers with 
laudanum of full pharmacopoeial strength, having in former days used 
a weaker preparation. Then again, some articles must be modified to 
suit the tastes of the public, for example, by imparting a certain color 
to a given preparation. Most of these excuses must be taken cum 
grano salts, but there are undoubtedly adulterations of long standing, 
such as "limed nutmegs," "bleached ginger," etc., that should be 
leniently dealt with at present, for it is well known that according to 
certain ancient methods of curing still practiced the kernels of nut- 
megs and the rhizomes of ginger are treated with lime to ward off the 
ravages of insects. Every possible effort should be made to have 
goods of this character labeled so as not to mislead the consumer. The 
great difficulty in making any concession whatever is that it might be 
construed as excusing the dealer's actions and thus embolden him in 
his insidious sophistry. 

When the physician is called to guide a patient through an illness 
his therapeutic knowledge is general^ called into pla} T , and he pre- 
scribes for the sufferer on the basis of pure drugs. If he is deceived 
in the quality of the agents delivered and administered, abnormal 
symptoms may arise for which the doctor is unable to account, and 
consequently he is placed in a very embarrassing position. As can 
readily be seen, most disastrous results may ensue, for which the 

7 



8 ADULTERATED DRUGS AND CHEMICALS. 

apothecary La responsible. Many a physician realizes the gravity of 
the situation, and in self-defense and for the welfare of his patients 
he prescribes certain brands of recognized purity or carries and pre- 
scribes his own remedies, made for him by reputable firms, rather than 
trusl the local druggist with the tilling of his prescriptions. 

The joint committee of tin 1 American Medical Association and the 
American Pharmaceutical Association, appointed to consider the feas- 
ibility of establishing a national bureau of medicines and foods, in its 
report to the latter body recommended the adoption of the following 
preamble and resolutions: 

Whereas the 1 la and medicines supplied in the United States do not so uniformly 

agree with proper standards of purity, quality, and strength as they should; and 

Whereas a degree of distrusl and want of confidence concerning the quality of 
Buch foods and medicines prevails to a discouraging extent: Therefore it is 

/. That a more perfectly organized system for remedying the above-men- 
tioned conditions than thai now existing should be devised and put into operation; 
and 

Resolved, That the American Pharmaceutical Association and the American Medical 
Association, acting In harmony with the United States Government authorities, con- 
stitute the most competent and trustworthy means for obtaining the object named. 

( )nly two of the resolutions are quoted, but they serve to show in a 
concise manner the present condition of affairs. 

During recent years Federal and State authorities have enacted laws 
which if properly amplified and conscientiously and intelligently 
enforced will in due time minimize the adulteration of medicinal agents 
and improve the quality of chemicals. These statutes generally recog- 
nize thai theiv are numerous methods by which the quality of a com- 
modity may be impaired. The object of this paper is to discuss some 
of these methods, cite examples taken from actual practice, and call 
the attention of the pharmaceutical and chemical world to the various 
forms of adulteration, which may be subdivided as follows: (1) Con- 
ventional, to Buil the tastes and demands of the public; (2) accidental 
or incidental, arising from environment, carelessness, or incompetence 
on the part of the producer or manufacturer or his agents; (3) arbi- 
trary, to comply with or take advantage of certain fixed, arbitrary 
standards; and ( + ) intentional, for gainful purposes and competition. 

CONVENTIONAL ADULTERATIONS. 

Conventional adulterations. Mich as silvered cochineal, bleached 
ginger, and the artificial coloring of many products, have been brought 
about in various ways. The original object in many cases undoubtedly 
was to trade on the credulity of the public, for it is a well-known fact 
that an attractive physical appearance is a great factor in the sale of 
goods, and color usually carries with it an idea of strength and quality. 
Such a firm footing have these factors secured that in some cases the 
adulterated article is selected rather than the pure. To illustrate, a 



INFERIOR DRUGS AND METHODS OF DECEPTION. 9 

few years ago, while exhibiting' a sample each of pure and weighted 
cochineal, a recent graduate of one of our well-known colleges, after 
looking them over thoroughly, selected the adulterated article as the 
genuine product. When informed of his error, somewhat chagrined 
at his mistake, he said, "It is the only kind I have ever seen and of 
course I thought it was the pure article." From this and similar 
experiences it would seem that some of our educational institutions 
are not exercising as much care as the}^ might in the selection of their 
material for instruction purposes. 

The artificial coloring of preparations is the most widespread of 
conventional adulterations. These pages will probably not come 
under the eyes of a single reader who is unable to enumerate a score 
of such products. To suggest a multitude of these goods it is only 
necessary to enumerate elixirs, tinctures, sirups, essences, pills, and 
tablets. As long as the harmless vegetable colors were used little 
cause for anxiety existed, but of late the danger line has been passed 
by the extensive use of aniline dyes. The finding of harmful coloring- 
agents in food products is a matter of common repute, and medicines 
are not exempt. It would probably not be desirable to interdict the 
use of harmless coloring agents, but their use should be discouraged. 
In cases where it is clearly evident that fraud is concealed by coloring 
agents, as in the preparation of vanilla extract from the chemical 
vanillin, dissolved in a suitable menstruum and colored with caramel, 
a suitable punishment should be provided. 

It is quite possible that an attractively colored preparation is more 
palatable than one that is not colored, but the nature of the coloring 
agent should, in such case, be plainly set forth on the label, unless it is 
part of a formula contained in some recognized authority like the 
Pharmacopoeia or the National Formulary. 

BLEACHED GINGER. 

The bleaching of ginger by covering the fingers with some white sub- 
stance, like calcium carbonate, is frequently done to cater to the fancy 
of certain customers. It also seems to be incidental to certain proc- 
esses of curing. In some cases, however, the prime motive is to 
conceal inferiority. The amount of coating added usually does not 
exceed 5 per cent, but the increase in price is about 15 per cent. In 
bleaching ginger considerable care must be exercised in the selection 
of the fingers, or the shrinkage due to loss of moisture will be equal 
to the amount of weighting material added. At all events the pur- 
chaser of bleached ginger pays more money^ and gets less ginger than 
if he purchased the unbleached variety. 



10 



ADULTERATED DRUGS AND CHEMICAL-. 



COTHINKAL. 



AvAM.Aiiii in 01 i ii k I'i Bl PRODI 

it --■.•in- that the oochineal industry i- grossly involved in adultera- 
tion, ati'l. according to some dealers, irretrievably lost to this practice. 
They contend that it i- almosl impossible to purchase a pure article on 
the "])«mi market, bui an investigation Bhows that this contention i ! not 
well founded. In fact, the pure product is so easily secured that adul- 
terated cochineal would be placed under the fraudulent form of 
adulteration if it were not well known that the consumer virtually 
knows only the silvered or commonrj adulterated variety. The object 
of the work don.- on cochineal was to ascertain, not the extent of the 
adulteration, l>ut how difficult it i- to obtain the pure article. It was 
found that pure cochineal was readily available when demanded. 
A Dumber of samples examined gave the following results: 

Analyse* of rorhineal. 









Mois- 
ture ni 


g matter. 


Price 

per 

pound. 




Kind. A-U Adulterant 


metric. 


vilutioii of 






.in 

rtby mat- 
ter. 

. 




100 
100 
100 


1.2 
1.0 

- 

1.3 
L9 


SO. 40 




.Ab 
. 4fi 






.50 




.4U 















Noa 3 and L56 represent goods delivered to th<- Bureau of Chem- 
istry without specification. No. L59 was sent with the belief that it 
was adulterated. Nos. L57, 158, and L65 were delivered as pure goods, 
and an examination proved such t«» be the case. On account of the 
high pric<-. the variable quality, and tin- customary adulteration of 
cochineal, suitable methods for readily determining it- quality are very 
desirable. 

Mjethodb of An - 

The per cent of ash is a fair index in determining the purity of coehi- 
ni-al. I»ut this factor can easily be circumvented by the addition of 
starch, mixing exhausted material with the pure article, or molding 
paste into small grains to resemble closely the outlines of the in- 
themselves. The ash of normal cochineal should uever exceed 6 per 

ci-nt. 

The most reliable procedure to determine the quality of cochineal 
i- to estimate the amount of carmine either eolorimetrically or by one 

of the oxidation methods. J. LOwenthal's" well-known method for 



"Zt.-l,. anal. Chem., 1877, 16: 179. 



INFERIOR DRUGS AND METHODS OF DECEPTION. 11 

the determination of tannin can be employed to advantage only when 
considerable work of this character is done. F. Penny's process 
appears to have many advocates. The basis of this method is the 
oxidation of the coloring material in an alkaline solution by means of 
a 1 per cent solution of potassium ferricyanid. It is executed by 
digesting- together, on a water bath, for one hour, 1 gram of powdered 
cochineal and 5 grams of caustic potash, dissolved in 20 cc of distilled 
water. Avoid dissipation of the water, dilute the resulting mixture 
to 100 cc, and titrate an aliquot part by means of the potassium fer- 
ricyanid solution. The carmine red color is changed to a brownish 
yellow. The transition of color is indistinct and the exact end reac- 
tion is difficult to determine. In this work 20 cc of cochineal solution 
were used for each titration. 

Except in cases where cochineal is to be used for special purposes, a 
simple colorimetric method gives satisfactory results. For this pur- 
pose the following process is suggested: 

Digest on the water bath for one hour, 1 gram of powdered cochi- 
neal and 1 gram of potassium hydroxid, dissolved in 20 cc of water; 
replenish the water as it evaporates and make the mixture up to 100 cc 
with distilled water. Dilute 10 cc of this solution to 400 cc. The 
color thus obtained, from a cochineal of known purity, is taken as the 
basis and called 100. If pure cochineal always possessed the same 
tinctorial value and were a well-known commercial article, the color 
obtained by the above procedure could be utilized as a standard. A 
readil} T available uniform standard is, however, found in a properly 
diluted aqueous solution of potassium permanganate. It has been 
found that by diluting 12.5 cc of a centinormal potassium permanga- 
nate solution (0.316 gram of pure potassium permanganate dissolved in 
1 liter of distilled water) to 100 cc, a tint of color is obtained, when 
observed in a Nessler tube held at a right angle to the eye of the worker, 
which is identical to that prepared from pure cochineal by the proc- 
ess described above. By adopting this potassium permanganate solu- 
tion as a standard, and calling it 100, the tinctorial value of every 
sample of cochineal can be ascertained and definitely expressed. If a 
sample of cochineal should be found in the future possessing a higher 
coloring equivalent than any met in this work, the standard of com- 
parison would not need to be changed, but could be expressed by 110, 
125, etc., as the case may be. 

According to the above method, Nos. 157, 158, and 165 are of good and 
equal quality, No. 159 is of fair quality, and Nos. 3 and 156 are decid- 
edly inferior, having only about one-half and two-thirds, respectively, 
the coloring value of a normal cochineal. A microscopic examination 
of No. 159 indicates that the silvering is due to rod-shaped bodies, 
like bacilli, but the usual bacterial stains would not effect them. It 

«Rept. Brit. Assoc. Advanc. Science, 1855, pt. 2, p. 68. 



12 ADULTERATED DRUGS AND CHEMICALS. 

is quite possible that the whitish appearance is due to a dried residue 
of cryptogamie plant growth. It i-- interesting to note that the results 
obtained by the potassium ferricyanid process run nearly parallel with 
the colorimetric data. 

The physical appearance of these conventionally adulterated articles 
has secured such a arm footing in the public mind that it is almost 
impossible to replace them by pure goods. To eradicate these deeply 
inculcated erroneous ideas will require years of patient effort by way 
of both exposure and education. 

ACCIDENTAL ADULTERATIONS. 

Accidental adulterations are very widespread, and it is frequently 
difficult to say where this form of adulteration ends and the fraudulent* 
lie<jin-. Crude drugs usually contain admixtures of twigs, stems, 
.Int. foreign leaves, and a host of other bodies. The Pharmacopoeia 

does not make any allowance for contaminations of this kind, but 
dealer- contend that such hypothetical requirements are purely aca- 
demical and have no place in the commercial world. The argument is 
also advanced thai certain drugs are collected by ignorant, semi-civil- 
ized people who can not i.e expected to eliminate impurities of this 
character. Excuses of this nature do not in any way relieve dealers 
and manufacturers from their responsibilities to the public. It is 

plainly their dut\ to handle and use only g Is of the proper quality. 

To what extent some of these foreign articles modify the primary 
action of a drug can not be conjectured. 

A certain few of the huge drug houses of this country are elimi- 
nating these impurities by garbling. When it is remembered that the 
foreign material frequently amounts to i y o per cent or more it is quite 
evident that the cost of garbled goods is materially increased and 
that dealer- in dean drug- are distinctly handicapped when brought 
into competition with those who handle inferior grades. It would 
probably be unjust to request a complete absence of foreign material, 
but a maximum limit could readily be fixed. A concerted effort should 
be made by all large manufacturers to establish a uniform high stand- 
ard for all drugs used by them either in the making of finished medic- 
inal remedies or for powdering. All purchases should be made on the 
basis of an adopted standard, paying only for the actual amount of 
good material in a consignment. 

By a recent act of Congress the Secretary of Agriculture is author- 
ized t«. investigate the quality of drugs imported into this country. 
The drug laboratory has already taken steps toward the securing of 
samples, which will be carefully investigated, in cooperation with the 
Bureau of Plant Industry. 

It would probably be too exacting to require a root to be freed from 
all extraneous matter, but an upper limit of ash should certainly be 



INFERIOR DRUGS AND METHODS OF DECEPTION. 13 

fixed. Some time ago a sample of golden seal root was received 
which was intended for powdering; it contained 23.8 per cent of ash 
and 2.02 per cent of hydrastine alkaloid, based on the air-dried mate- 
rial. A normal root should not contain more than 10 per cent of ash 
and not less than 2.5 per cent of hydrastine alkaloid. With golden 
seal at 60 cents per pound this dirt is a profitable addition for someone. 
Certain leaves almost always contain a considerable amount of for- 
eign matter. Chimaphilla leaves have been seen which were mixed 
with 25 per cent of stems. A sample of jaborandi leaves recently 
examined contained not less than 16 per cent of twigs and stems. A 
coca leaf sample on assay indicated 0.52 per cent of cocaine alkaloid, 
but the leaf was mixed with at least 18 per cent of foreign material. 
No valid excuse exists for this evil. Coca leaves containing as little as 
3 per cent of foreign matter are readily available. A sample of cubeb 
berries on examination gave the following results: Stems, 15 per cent; 
worthless berries, 11 per cent; oil, 6.38 per cent. The physical 
appearance of the oil was good, its specific gravit}^ 0.9384, and optical 
rotation —34.6°. The gravit} T is a little high but can hardly be con- 
sidered abnormal. Good berries should yield not less than 12 per 
cent of oil. 

DETERIORATED DRUGS. 

The sample of cubeb berries referred to serves as an excellent 
example of transition between drugs containing foreign admixtures 
and those that have deteriorated by ag'e or manner of keeping. To 
what extent these cheap, inferior, and in some cases worthless goods 
are used it is difficult to ascertain, but from information vouchsafed 
by brokers, drug millers, and manufacturers, this practice obtains to 
a considerable extent all about us. Deteriorations are incidental to 
the drug business, but the use of such goods, knowingly, in the man- 
ner indicated, is fraudulent, and what makes this practice so extremely 
reprehensible is the fact that it is very difficult, if not impossible, to 
detect inferior material of this character when powdered with goods 
of prime quality. 

Articles particularly susceptible to change due to time are those con- 
taining essential oils, such as cinnamon bark, clove buds, lavender 
flowers, peppermint herb, sandal-wood chips, etc. A hundred-pound 
package of cinnamon-bark chips when submitted to distillation yielded 
only enough oil to impart a distinct flavor of cinnamon to 5 gallons of 
the aqueous distillate. Potent drugs with only a trace of alkaloids, 
due to old age, improper collection, or damage in transportation, are 
frequently used. Old jaborandi leaves deficient in alkaloidal strength 
are met with at times. Belladonna leaves improperly collected are 
not uncommon, and damaged coca leaves are occasionally placed on 
the market. 



14 ADULTERATED WBTTG8 AM) CHEMICALS. 

•V. I'." CMIvMICAlx 

No less an authority than F. W. Morley during an interview said: 
••It i- virtually impossible to make a chemical absolutely 100 per cent 
pure." From this it would seem that we must expect to find a small 
amount of foreign material in all chemicals. Experience shows such 
to be the case. These Impurities arc usually incidental to the process 
of manufacture, but when the amounts are excessive it must he ascribed 
to cither carelessness, ignorance, or a desire on the part of the manu- 
facturer to prepare a cheaper article at the expense of purity. 

Chemical reagents arc usually supplied as being chemically pure, 
•'('. 1'." This designation was formerly supposed to mean, as it now 
should, a chemical «>f a high degree of purity. Whether this quality 
of chemicals was ever of a higher degree of purity than at present is 
difficult t<> ascertain. Occasionally we find a note in chemical litera- 
ture to tl fleet i hat certain chemicals represented as free from 

impurities contained appreciable quantities of foreign matter. For 
example, ( !lassen calls attention to two samples of '■chemically pure" 
bismuth, sold for "scientific purposes," one of which contained -2 per 
cent of lead and the other L.5 per cent of copper and 0.5 per cent of 
iron. Everj sample of bismuth ever examined by the writer con- 
tained traces of arsenic and iron. Notwithstanding the fact that 
great improvements have been made in the manufacture of chemicals 

within recent years, the stage has not yet been reached in which 

chemicals are absolutely \'r><- from all impurities. It is true some of 

them will indicate a purity of 100 per cent, but this i-. usually due 
to the impurities ' m one chemical offsetting those in another, or to 
limitation- of analytical methods. For example, recently a purchase 

of high-grade potassium permanganate was tested and found to ana- 
lyze LOO per cent pure, and yet the chemical contained traces of 
nitrate- an. I chlorids. The oxalic acid solution was prepared from 
oxalic acid that had been recrystallized in the laboratory with every 
possible precaution, and a careful examination showed that it was free 
from all impurities ascertainable by chemical analysis. Furthermore, 
the normal solution of oxalic acid was tested as to strength by the 
best methods and found to be correct. 

The designation "C. P." as used at presenl is not only meaningless 
and worthless, but misleading in the extreme. Chemicals of the 
poorest character are masked ""('. P." Manufacturers use the term 
carelessly, and dealer-, w ill attach it to any article of a chemical nature 
that thej think will thus be made more attractive. Such dealings are 
an imposition on the consumer and unfair to honest competitors. 
Sometime ago an examination was made of sodium carbonate crystals, 
C. P.. delivered on a competitive bid, which were found to be about 
equal in quality to commercial English sal soda. Circumstantial evi- 



INFERIOR DRUGS AND METHODS OF DECEPTION. 15 

fiance pointed strongly to the conclusion that this dealer had simply 
marked the English brand with the classical abbreviation "C. P." and 
delivered it as such. Again, the writer has known of carloads of 
C. P. glycerin, shipped in iron drums, that contained a sediment 
consisting of iron scales, fibrous material, and other debris. These 
goods were also delivered on contract, awarded on sample submitted 
and competitive bid. If these consignments had not been examined 
on delivery they would have been accepted without question, but after 
their true nature became known they were promptly rejected. Honest 
dealers handling goods of prime quality can not successfully compete 
with articles of this character unless each consignment is examined. 

A few more cases will be sufficient to show the quality of some of 
the C. P. chemicals frequently delivered. C. P. gtycerin often con- 
tains arsenic and certain bodies that reduce an alkaline copper solution, 
and invariably contains volatile fatty acids. One sample of potassium 
iodid, C. P., was found to be contaminated with sulphates, iodates, 
and sodium compounds. It also contained 1.5 per cent of chlorid, 
and 5 grams required 3 cc of decinormal acid to neutralize the alka- 
linit3 r . A sample of potassium bisulphate C. P. contained only 33 per 
cent of the acid sulphate. Some calcium oxid C. P. was found to 
contain iron, aluminum, magnesium, sulphate, and siliceous matter, 
being virtually no better than ordinaiy commercial quicklime. A 
sample of calcium chlorid C. P. was found to be contaminated with 
iron, aluminum, and magnesium, and was highly alkaline to litmus 
paper. Such articles would certainly be objectionable for analytical 
work. 

Certain dealers, laboring under the delusion of hypercritical stand- 
ards, have sought shelter behind the very elastic term "pure" and are 
supplying the market with chemicals which they think are sufficiently 
pure for all practical purposes. The term "pure" conveys distinctly 
different meanings to the artisan, assayer, broker, chemist, manufac- 
turer, photographer, physician, and toxicologist. As a rule, these 
consumers do not call for chemicals free from all conceivable impurities, 
but demand the absence of certain specified contaminations which are 
detrimental in special work. The toxicologist must have his zinc free 
from arsenic, phosphorus, antimon} T , and sulphur, while traces of 
copper, carbon, or lead may not be objectionable. 

There are a number of other terms used which at present convey 
very little information; they are Purum, Purissimum, Purified, 
Twice Purified, and Absolute^ Chemicalh" Pure; and even IT. S. P., 
Br. P., and Ph. Ger. IV, are indifferentby employed. Within recent 
years manufacturers have adopted a custom of marking some of their 
chemically pure chemicals "Free from manganese,'' "Free from 
sulphur," " Free from iron," "Arsenic free," "Free from silver," 



16 ADULTERATED DRUGS AND CHEMICALS. 

and "Strictly chemically pure, freefrom N.andS." The marking of 
chemicals as free from certain imparities is certainly a step in the 
right direction, but the great difficulty is that many of these chemicals 
are free from these impurities only on the label. A recent consign- 
ment of copper sulphate t<> be used in sugar analysis, delivered to the 
Bureau <»t' Chemistry on 1 1 1 « - specification that it must be strictly free 
from iron, was -><> labeled, but nevertheless contained this impurity in 
appreciable quantities. A purchase of magnesium oxid guaranteed 
to be free from sulphur and so labeled contained over 2 percent of 
sulphur calculated as anhydrous sodium sulphate, and goods labeled 
"Chemically purr sulphuric acid, arsenic free," frequently contain 
this impurity . 

In \ -iew of the above facts it is quite evident, first, that "C. P," or 
"Chemically pure." with allits qualifying adjectives, at present means 
nothing, and it- fraudulent use should be prohibited; second, that no 
chemical should l>e accepted as free from a certain impurity simply 
because the package is so labeled; and. third, that certain specific 
standards for chemical reagents should be established. Such reagents 
should be free from all undesirable or detrimental contaminations, 
and this fact should be set forth on the label. It is well known that 
many original packages are not marked at all except by the private 
mark of the manufacturer. A Federal law requiring that every 
package of chemicals be properly labeled a- t<> name and quality would 
remedj this practice. V. Coblentz, in this connection, well says: 
"The indiscriminate labeling of chemicals without qualification as to 
degree of purity should bj all means be discouraged as being a loose 
practice through which legal responsibilities may be evaded." 

ADULTERATIONS RESULTING FROM ARBITRARY STANDARDS. 

The argument i- occasionally advanced that arbitrary standards are 
direct incentives t<> fraudulent dealings. Fluid extract of mix vomica 
prepared from a bean containing ~J.'> per cent of total alkaloid- is 
diluted, t<> conform t<. a standard, so that it contains only 1.5 per cent 
of alkaloids. Milk drain- reduce milk containing "> percent of fat, 
so as to pa— a :: percent standard. The former is considered right, 
the latter reprehensible to a high degree. In reality the one does not 
appear to be any worse than the other. 

The United State- Pharmacopoeia prescribes an upper and a lower 
limit of morphine for powdered opium, but no provisions are made to 
reduce an opium containing more than L5 per cent of morphine, the 
highest amount permissible, so as to conform to the proper require- 
ments It i- not uncommon to meet with powdered opium containing 
over L5 percent of morphine, and dealers are compelled in self-defense 
to reduce it to the proper strength by mixing it with opium of a lower 



INFERIOR DRUGS AND METHODS OF DECEPTION. 17 

grade, or to use it in the manufacture of other medicinal remedies 
containing morphine. If the manufacturer places powdered opium 
on the market containing more than 15 per cent of morphine, he 
becomes liable to punishment, and if he dilutes it to the proper 
strength with a detectable diluent many State laws consider him cul- 
pable. In fixing standards of the above type it is desirable to provide 
for contingencies of this character. 

Some dealers maintain that the pharmacopoeial requirements of cer- 
tain oils are abnormal and that adulteration must be resorted to if oils 
of the desired quality are supplied. Much capital is made of this in 
certain quarters, bj^ quoting such oils as bay, coriander, and pimento, 
"compounded to conform to the requirements of U. S. P. 1890," at 
from 30 to 60 per cent below the price asked for pure oils which are 
not expected to comply with the pharmacopoeial standards. 

ANALYSES OF CERTAIN OILS AND POTASSIUM CYANIDS. 

The most important factor in judging the quality of oil of bay, 
aside from its peculiar odor, is the specific gravity, which should lie, 
according to the Pharmacopoeia, between 0.975 and 0.990, at 15° C. 
An examination of ten samples of pure oil of bay, obtained directly 
from the distillers, gave specific gravities varying from 0.958 to 
0.980. All but two fell below the lower limit. Other recognized 
authorities allow a lower limit of 0.965. Three of the above samples 
fell below this standard, being 0.958, 0.9627, and 0.964, respectively. 
On submitting 511 pounds of bay leaves to steam distillation, 12.5 
pounds of light and heavy oils mixed were obtained, which after aging- 
one year had a specific gravity of 0.955. It would therefore seem 
that the specific gravity of the Pharmacopoeia for oil of bay is a little 
too high. 

Six samples of coriander-seed oil were examined, of which three 
were marked pure, two were distilled by the writer, and all complied 
with the U. S. P. requirements. The sixth was marked "German," 
and proved to be adulterated. The pharmacopoeial standard is there- 
fore not far from the truth. 

Six samples of oil of pimento berries were tested. Their specific 
gravities were as follows: 1.0194, 1.0510, 1.0280, 1.034, 1.040, and 
1.035. In other respects these oils complied with the pharmacopoeial 
requirements. The first two were labeled, "Made to conform to the 
U. S. P. requirements." The last was distilled b}*- the writer, and the 
others were secured from prominent distillers in this country and 
guaranteed pure. The Pharmacopoeia requires the specific gravity to 
fall between 1.045 and 1.055, but "Die Aetherische Oele," by Gilde- 
meister and 'Hoffmann, recognizes a specific gravity as low as 1.024. 
While the specific gravity is, to a certain extent, an indication as to 

13528— No. 80—04 2 



L8 



ADULTERATED DRUGS AND CHEMICALS 



it would not be wis 
adulterated simply 



•. in view of the 
because it bad a 



the amount of eugenol present, 
aboi e Facts, to pronounce an oi 
specific gravity below L.045. 

Potassium cyanid '. ,s to LOO per rent pure has assumed considerable 
commercial importance. In ordering this article it is customary to 
Bpecify the per cent of cyanid only. For 6nancial and technical 
reasons potassium <•> anid is largely mixed with sodium cyanid. Tfrere 
can be no real < > ( » j « ■ < • t i « > 1 1 to this practice, if the goods arc properly 
represented, but a mixture of these two cyanids should not be deliv- 
ered for 98 to LOO per cent potassium cyanid. In determining the 
percentage of potassium cyanid in a mixture of this character the 
results will be above LOO per cent in proportion to the amount of 
sodium cyanid present. In order to meet this difficulty manufacturers 
add, or do not remove, certain inert substances, which usually consist 
of carbonates, chloride, or mixtures () t' both. 

An examination of four samples of potassium cyanid, labeled 98 to 
LOO per cent pure, gave the following results: 

Anal 100 per cent potassium cyanid. 



Sami ulated 


cyanid. 


Sodium 
cyanid. 


Potassium 
carbonate, 

etc. [by 
difference). 


Moisture 


Sodium 
chlorid. 


1 .... l"l 

111. 19 






Per cent. 
12.82 


14.27 






i 


1.58 1.66 



Allot' the above samples represent imported goods. The results 
are self-explanatory. No valid reason for the practice of mixing the 
cyanids in the manner shown and Belling the mixture as potassium 

cyanid has thu- far I n offered by manufacturer-. 



METHODS OF ESTIMATING CHLORIDS IN SOLUBLE CYANID8. 

The present methods for detecting and estimating chlorids in the 
soluble cyanids are not satisfactory. It is usually stated that silver 
cyanid i- soluble in concentrated nitric acid, whereas silver chlorid is 
insoluble, but in practice it is not safe to rely on this test. The fusion 
method i- useful but dangerous. It consists in heating to redness an 
intimate mixture of 1 gram each of the cyanid and potassium nitrate 
and 5 -rain- of potassium carbonate. The carbonate and nitrate must 
be free from chlorids. In this mixture an extremely efficient oxidiz- 
ing agent and one of the best-known reducing agents are brought 
together. When the mixture is fused, there is a more or less vig- 
orous chemical reaction, and frequently an explosion results. A more 
expeditious and satisfactory method would therefore be welcome. 

The gravimetric method on the next page is based on the fact that 
cyanid- reduce permanganates. 



INFERIOR DRUGS AND METHODS OF DECEPTION. 19 

In a 250 cc beaker, containing 150 cc of water, dissolve approx- 
imately 1 gram (accurately weighed) of the cyanid. Heat to boil- 
ing, then cautiously add about 2 grams of potassium permanganate or 
such a quantity that the solution after having been heated for one-half 
hour on the steam bath is still distinctly pink. Destroy the excess of 
potassium permangauate with oxalic acid, heat the mixture a few 
minutes on the water bath, and the precipitate will subside, leaving a 
colorless layer of liquid. Filter the solution hot, wash the precipitate 
on the filter paper with 200 cc of hot water, mix the filtrates, render 
distinctly acid with nitric acid, and heat the mixture to boiling. In 
this solution the chlorids are estimated in the customary manner. 

Mr. J. K. Haywood, chief of the insecticide and agricultural water 
laboratory of the Bureau of Chemistry, employs a volumetric method 
with satisfactory results. It has been carefully compared with the 
above gravimetric process and found to accord with it uniformly. 
The method is as follows: 

Weigh accurately in a weighing bottle about 10 grams of the sub- 
stance, dissolve in water, and make up accurately to 1 liter. In an 
aliquot part of this solution estimate the cyanogen by titrating with a 
decinormal silver nitrate solution. The end reaction is shown by the 
appearance of a white cloudiness in the solution. Now add potassium 
chromate, as indicator, and titrate with the standard solution of silver 
nitrate until the appearance of the usual reddish-brown color of silver 
chromate. 

The reactions involved in the above method are represented by the 
following equations: 

(1) AgN0 3 +2KCN=AgCNKCN+KN0 3 . 

(2) AgCNKCN+AgN0 3 =2AgCN+KN0 3 . 

(3) NaCl+AgN0 8 =AgCl+NaNOs. 

Representing the number of cubic centimeters of silver nitrate solu- 
tion used in the first titration by A and the number of cubic centi- 
meters used in the second titration by B, then B— A equals the number 
of cubic centimeters of decinormal silver nitrate solution required to 
combine with the chlorids present, while the amount of cyanogen can 
be calculated from A, as indicated hj the first equation given. 

INTENTIONAL ADULTERATIONS. 

With very few exceptions the underlying motive of all intentional 
adulterations is monetary gain. Some of the sophistications consid- 
ered above appear to have some superficial excuse for existing, but 
those here enumerated as intentional are deliberately premeditated 
misrepresentations, and should be dealt with summarily. In this 
category comes the potassium cyanid reported above. Other instances 
are: Borax diluted with sodium bicarbonate; cornstarch delivered when 
St. Vincent arrowroot is asked for; prime quality drugs mixed with 



20 ADULTERATED DBUG8 A.ND CHEMICALS. 

inferior or partially exhausted goods; spurious sandalwood oil con- 
taining chloroform added \<> raise the specific gravity and to increase 
tlir apparent content of santalol; powdered drugs in the preparation 
of which inert and deteriorated products have been used; beeswax 
w ith its Qumerous adulterations; turpentine diluted with kerosene, etc 

A sample of beeswax recently examined was found to contain 33 
percent of cassava starch. This variety of starch indicated that the 
adulteration was of southern origin. On inquiry it was found that 
about $800 worth of this fraudulent material had passed through the 
New York custom-house, having been imported from Mexico. 

Another sample of beeswax on examination gave the following' 
results: Melting point, 61.5 C; specific gravity at 1.". ('.. 0.959; 
acid Dumber, 14. -J: ether Dumber, 73.6. These oumbers do not mate- 
rially differ from those usually recognized as normal for pure beeswax, 
except tin- acid number, which i- a little low. A qualitative exami- 
nation showed that this article consisted, for the greater part, of a 
high melting point ceresinand .la pan wax. the mixture being probably 
flavored artificially t" resemble the genuine product. New York i- 
the home .if the apiar\ which produced t)ii- remarkable beeswax. 

The adulteration of beeswax with starch i- discouraging, because it 
shows that the days of gross sophistication are not past; but to find 
a scientifically prepared mixture closely resembling beeswax is most 
deplorable, because it indicates that men of education are using their 
talent- t«» Ben e a dishonest purpose. 

The drug laboratory has in it- possession a -mall amount of a 
lla\ oring agent, w Inch ha- been exploited as of much service in beeswax 
adulteration, but the nature of it- composition has not as yet been 
determined. 

Twenty-fix e per cent of all turpentine, a- usually purchased in -mall 

package-, i- Liberally adulterated with kerosene. The present analyti- 
cal methods d<> not appear to he sufficiently refined to detect this adul- 
terant with certainty when present in -mall quantities. Investigations 
are under way at present which it i- hoped will remedy this defect. 

-II TINGS AM. SWEEPINGS. 

In the handling of drugs more or less of the finer particles escape 
from the hale-, and in the larger warehouses the practice has been 
established of collecting tin- material from the floor-, a- occasion 
requires, and offering it t<> the trade at a low figure. The conditions 
under which these -weeping- ami sittings are accumulated and col- 
1 naturally lead t<> the belief that they are likely to be contami- 
i \>> a considerable degree. Products of the above character 
commonly met with are the cinchona hark-, cochineal dust, pepper, 
tea. and senna Lea 



INFERIOR DRUGS AND METHODS OF DECEPTION. 21 

Some of the sweepings and sittings are utilized in extracting certain 
active principles, like caffeine from tea sweepings, and certainty 
nothing could be said against an economy of this kind, but the practice 
of using articles of this character in the manufacture of medicinal 
preparations should certainly be discountenanced. Some manufac 
turers frankly admit that this practice obtains in their works, but 
maintain that these goods are "just as good" as those for which a 
high price is paid. 

Three bales of calisaya bark sittings, all containing foreign material, 
on examination gave the following results: The per cent of total alka- 
loids was 0.47, 3.6, and 4.7. The per cent of ether-soluble alkaloids 
was not determined in the first bale recorded, and was 1.9 and 2.7, 
respectivel}- , in the last two. A good calisaya bark should not contain 
less than 6 per cent of total alkaloids nor less than 3.5 per cent of 
ether-soluble alkaloids. 

Every bale of senna sittings and every bag of tea sweepings exam- 
ined contained a goodly proportion of extraneous matter. Broken 
senna leaves are usualty of good quality. 

A COMMON METHOD OF DECEPTION. 

A verjr significant editorial appeared in the British Food Journal," 
from which the following extract is taken: 

The substitution of an imitation of some kind for the article actually asked for or 
desired by the purchaser is a particularly mean form of deception which is practiced 
nowadays to an almost incredible extent. It ia astonishing and mournful that so 
many persons should be concerned in the initiation, fostering, and carrying on of so 
shameful a system, and that others are found who in speech and print seem willing 
to lend to it either their countenance or condonation. 

Still more reprehensible is the practice of submitting a sample of 
prime quality and then, on receipt of an order, delivering goods of an 
inferior grade. 

Some may think that the above method of deception does not obtain 
to any extent, but only a superficial investigation will show that it 
permeates many lines of business, and those who are responsible for 
the quality of the medicinal remedies supplied the unfortunate sick 
should ever exercise eternal vigilance. The following examples, 
which are tj^pical of this practice, should serve to banish the remotest 
doubt. A sample of belladonna leaves contained by acid titration 
0.438 per cent of total alkaloids. On receipt of the consignment 
delivered as per sample submitted, nine bales were tested with the fol- 
lowing results: 0.12, 0.14, 0.11, 0.10, 0.13, 0.12, 0.13, 0.30, 0.11 per cent 
of total alkaloids. A sample of potassium bromid complied with 
U. S. P., 1890, requirements. The goods supplied were inferior in 

«1903, vol. 5, p. 97. 



22 ADULTERATED DETJG8 AND CHEMICALS. 

every respect A podophyllin sample was of U. S. P. quality, but 
the article delivered contained much material insoluble in alcohol. A 
linseed-meal -ample contained 33 per cent of pure oil. After placing 
;tn older on the strength of the sample, two carloads were delivered, 
which, on examination, proved to contain on the average 35 percent 
of oil, having the following properties: Specific gravity at 15 ('.. 
ii. '.to;,;,-, acid Dumber, 6; saponification number, 99.7. The oil 
extracted from the linseed meal was highly adulterated with mineral 
oil. which was added to the flaxseed meal after a part of the natural 
oil had been expressed. A sample of oil of wormwood of good qual- 
ity was submitted, hut the goods delivered were adulterated with 
turpentine. A sample of tea sweepings submitted contained 2.64 per 
cent of caffeine alkaloid. A ton subsequently delivered contained only 
L.6 per cent of tlii- alkaloid. A -ample of caramel possessed a color- 
ing equivalent of loo. and gave good tests in every respect. On 
examining a delivery of about 5,000 pounds it was found to have a 
coloring equivalent of only 80, and deported itself badly in every way. 
These examples could be largely extended, hut the above fully illus- 
trate existing conditions. 

It will be observed thai most of the example- cited represent the 
larger transactions and usually involve manufacturers and producers. 
.Many members of the American Pharmaceutical Association and the 
National Whole-ale Druggists' Association, and some of the besi 
informed manufacturers and jobbers, have placed themselves on record 
a- conversant with these undesirable methods and anxious to prevent 
their use, hut they are greatly handicapped by competition. Such 
men bope to see the day when all druggists, retail or wholesale, will 
be compelled by some competent authority to deal only in high-class 
medicinal agents. 



II.— ROSE GERANIUM OIL AND ITS SUBSTITUTES. 

In spite of the great advance made in the chemistry of essential oils 
during- the past decade, ample evidence can readily be collected to 
show that this is as yet a fertile field for the adulterator. Many 
kinds of manipulators are found, from the tyro who • endeavors to 
palm off oil of French turpentine for oil of rue, and the distiller who 
sprinkles his rose leaves with geranium oil before, distilling, to the 
chemist who is an abettor to the use of acetin and glycerin in volatile 
oils for the purpose of increasing the apparent content of ester and 
alcohol, respectively. 

By referring to the various price lists it will be found that the quo- 
tations for the geranium oils vary from $12 per pound for the Spanish 
to $2.25 for the Turkish oil; and ginger-grass oil, which is conceded to 
be only another name for an inferior Turkish oil, sometimes highly 
adulterated, is quoted at $1.10 per pound. Certainly here seems to be 
a great opportunity for the clever manipulator, and aside from the 
assistance of a well-trained nasal organ, let us see what are the proba- 
bilities of detecting such adulteration. 

Rose geranium oil is a colorless, yellowish, greenish, or brownish 
liquid, depending on the manner of distillation and storage, and has a 
pleasant rose-like odor. Its specific gravity varies from 0.8878 to 
0.9073; optical rotation in a 100 mm tube, —6° to —16°; ester, calcu- 
lated as geranyl tiglinate, varies from 8 to 42 per cent. All varieties 
are soluble in 2 to 3 volumes of 70 per cent alcohol, except the Span- 
ish, which is rendered turbid by the presence of a small amount of 
separated paraffin. The chief constituents are geraniol and citronellol, 
the total content of which, both free and combined, varies from 60 to 85 
per cent. The former usually exists in much the greater proportion. 

Turkish or Indian geranium oil, also known as palma rosa, Indian 
grass oil, and rusa oil, usually closely resembles rose geranium oil in 
physical appearance, solubility, specific gravity, and percentage con- 
tent of alcohols and esters. In odor there is frequently a close resem- 
blance and the optical rotation varies from +2° to —2°. 

Ginger-grass oil is supposed to be an inferior quality of palma rosa, 
and its properties, therefore, should very closely resemble those of 
the latter oil, excepting possibly its odor, unless it is highly diluted 
with turpentine or mineral oil, as is frequently the case. 

It can readily be seen that a judicious mixer could combine oils 
possessing the properties described above so as to bewilder a chemist, 
even though he were well versed in the chemistry of essential oils. 

23 



24 



AIM I.TKRATK1) DRUGS AND CHEMICALS. 



Jeancard and Satie a have studied these oils to some extent, and 
think they can distinguish between them by their contents. The fol- 
lowing table i> taken from their work; 

Analytical <l<<t<i on pure geranium oils. 



Rotation c nn „ nifi 
Density atl6°C. S ; *' " f " 
atl5°C. inlOO «g« 



Cannes .. 
Spain — 
Corsica .. 
Africa ... 
Bourbon. 
India.... 



o. 8972 


-9.40 


.'.hit;; 


-7.30 


.9012 


-8.00 


.9006 


-8.06 


.8906 


8.20 




- .48 



54. 00 
65. 80 
60. 20 
65. 80 
74.00 
'43. 00 



Per rent. 
9. 80 
7. M 
7.00 
8.08 
6.65 
11.30 



Per cent. 
66.31 
66.23 
68.55 
63.19 
71.28 
84.62 



'I'lic percent of esters and alcohols is based on the formula? C 12 H 20 O 2 
and C 10 H 18 < ). respectively. 

In \ iiw of the fact that the highest-grade oils grow in certain locali- 
ties only and bring fancy prices, the opinion is ventured that it would 
not be -alV to deduce any general statement from the above results, 
excepl in the case of Indian oil. 

Some time ago the \\ riter received a number of samples of geranium 
oils in original packages hearing the labels of the largest and best- 
known essential-oil dealers in the world, with the request that an 
opinion he given as t<> their purity and quality. On submitting the 
samples t<> an examination the results tabulated below were obtained: 
.1 iinl yst s of geranium and allied "Us. 



Specific Acid 
gravity nuin- 



Estera 

as tigli- 

nate. 



Alco- 
hols. 



Opt. rot. 

in 100 

mm 

tube at 

•jo r. 



Solubility in 70 percent 
alcohol. 



African ill .. 
African (2).. 
African (3) . 
African (4).. 
Algerian ii> . 
Algerian .2.. 
Reunion 



Palma rose 

Turkish (1) 

Turkish (2) 

Ginger g 
Ginger grass (2) 
Rbodonol II 



Greenish yellow. 
Lemon > ellow . . . 
' irange yellow ... 
Lemon yellow . . . 

.In 

Colorless 

Lemon yellow... 

Orange yellow... 
Lemon yellow. .. 

.In 

do 

do 

Colorless 



0.8901 
.8916 

.9319 

. SOS] 

.8964 
8878 



91 u 
.9154 
.9213 



1.51 

O.IK) 

B.09 

1. 17 

8.20 
2.87 
B. 28 

L.80 

4.13 

2. II 
1.50 
3.88 



/'- ,■ Ct. 
20.48 
28.96 
18.98 
95.00 

a78 v, 
:;:;. m 
36. 16 
28. 89 
22. :;o 

B18.60 
12.13 

B10.06 

i 11.25 
"11.72 
r 8.07 
i a 6. 69 
L46 
[al.20 
\ 9.00 
" 7. 12 



Perct. 
76.06 

63. !'.• 

12.3 1 

In. 08 

t;:.. .-.; 
7:;. 1 1 

72.13 

J s. 1.75 



- 6.73 

- 8.41 
-19.20 

- 7.70 



Soluble in 2 volumes. 
Insoluble in 10 volumes. 
Do. 



Soluble in 1} volumes. 
17.0(1 Insoluble in 10 volumes. 
9. 60 Soluble in 2^ volumes. 
7. on Soluble in 2 volumes. 






50.00 


-50. 70 


72. 93 


+ 1.91 


20. 18 


-69.13 


21. 77 


-65.00 


r 


20. 9 



Do. 
Insoluble in 10 volumes. 
Soluble in 2 volumes. 
Insoluble in 10 volumes. 

Do. 

Soluble in 2 volumes; 
insoluble in more. 



Per cenl of ester calculated asgeranyl acetate. 



The acid number was determined by dissolving a given weight of 
the oil in strong alcohol, in which all the oils were soluble in all pro- 
portions, and titrating with decinormal alcoholic potash, at the ordi- 
nary temperature, using phenolphthalein as indicator. The figures 



a Bui. Boa Chini., L900 (3), 23: 37. 



ROSE GERANIUM OIL AND ITS SUBSTITUTES. 25 

indicate the number of milligrams of potassium hydroxid required 
to neutralize the acidity of one gram of oil. The esters were esti- 
mated by adding an excess of alcoholic potash to the above solution, 
heating to boiling with a reflux condenser for about one hour, then 
titrating back the excess of alkali by means of decinormal acid. From 
the amount of alkali consumed the necessary calculations can readily 
be made, either as geranyl tiglinate (C 10 H 17 CO 2 C 4 BL) or geranyl 
acetate (C 10 H 17 CO. 2 CH 3 ), as the case may require. The percentage of 
alcohol, free or combined, was determined by acetylizing a given 
Weight of oil with an equal amount of acetic anhydrid, in the 
presence of fused sodium acetate. The acetylized product was 
purified by washing with water, and rendered anhydrous by means of 
fused sodium sulphate. A given weight of the acetylized oil was then 
saponified, as outlined above for determining esters, and from the data 
thus secured the desired calculations were made. 

In computing the amount of alcohol, both free and combined, in 
geranium oil. it must be remembered that the chief ester of the natural 
oil is a tiglinate, and on acetylizing with acetic anhydrid the free alco- 
hols are converted into acetic esters. We therefore have a mixture 
of esters on which to base our calculations. The percentages of 
alcohols given in the table above were computed from the mixed esters. 
The question might arise as to whether any of the tiglinic group was 
replaced by the acetyl group, but this inquiry can not be answered 
here. 

The first African oil, the second Algerian oil, and the Reunion oil are 
normal in every respect. The African oil No. '2 and the Algerian oil 
Xo. 1 can be considered normal except as to solubility, and it is doubt- 
ful whether these oils can justly be considered adulterated. The third 
African oil is low in alcohol content, high in optical rotation, and 
insoluble in the proper amount of 70 per cent alcohol. The fourth 
African oil is a spurious product, which did not respond affirmatively 
for a hydroxy! group when tested by means of acetyl chlorid in the 
conventional manner, thus indicating- the absence of any alcohol. The 
palma rosaoil and the Turkish oil Xo. 2 are both normal India products, 
while the first Turkish oil is abnormal. Both of the ginger-grass oils 
are entirely different from anything described in literature. Judging 
from the high specific gravities and high optical rotations, these ginger- 
grass oils are not adulterated with either turpentine or mineral oil. 
The last oil named, Rhodonol II, is apparently a fairly pure geraniol. 

It is clearly evident from the data obtained in this investigation and 
other work on record that a scientific adulterator could readily mix 
some of the cheaper geranium oils with the expensive, high-grade 
products without much fear of detection by the analytical methods at 
present available. Apparently the only satisfactory procedure at our 
disposal for securing the proper quality of geranium oil is the use of 
well-trained olfactories. 



Ill— PHENACETIN: METHODS OF ANALYSIS AND COMMER- 
CIAL STATUS. 

HISTORICAL REVIEW. 

On reviewing the history of phenacetin it soon becomes apparent 
that, like many other useful discoveries, it was not the achievement 
of a single individual nor of a certain time, but was gradually evolved 
by the successive efforts of many minds, stimulated by the progress of 
correlated branches of science. It was, however, due to the patient 
efforts of O. Hinsberg and his associates that the production of this 
article on a commercial scale was made possible and its great medicinal 
value became known to the world. 

The germ of phenacetin was sown by the celebrated French chem- 
ist, A. Cahours, during the course of a series of valuable investi- 
gations extending over a number of years. In 1843 a appeared his 
"Recherches sur l'huile de Gaultheria procumbens," which work was 
persistently continued until 1849, b when he announced the discovery 
of phenetol (C 6 H 5 OC 2 H 5 , phenol ethyl ether), mononitrophenetol 
(C 6 H 4 N0 2 OC 2 H 5 ), and phenetidin (C u H 9 N0 2 C 2 H 2 , old nomenclature). 
Two methods for preparing phenetol were given; one by heating 
together ethyl salicylate and baryta, and the other by simply heating 
barium ethyl salicylate. 

Following up a suggestion of Cahours, G. Baly, c at the request of 
A. W. Hofmann, prepared phenetol by the first method described 
above, but called it "salithol." Baly presented his work to the Lon- 
don Chemical Societ}^ December 1, 1818, but it did not appear in the 
society's official organ until 1850. It is interesting to note in this 
connection that several foreign journals printed the article in 1819, 
giving the Quarterly Journal of the Chemical Society credit for an 
article that did not appear in its columns until nearly a year afterwards. 

In 1851 Cahours ^ prepared phenetol by heating potassium phenolate 
and ethyl iodid together in a sealed tube at from 100° to 120° C. The 
following year appeared C. Gerhard tV classic "Recherches sur les 
acides organique anhydres." In this investigation we find prepared 

fflComp. rend., 1843, 16: 853; J. prakt. Chem., 29: 197. 

&Ann. Chim. Phys., 1849 (3), 27:439; J. prakt. Chem., 1850, 49:262; Ann. 
(Liebig), 74: 314. 

c Quart. J. Chem. Soc, 1850, 2: 28; J. prakt. Chem., 1849, 47: 419. 
dComp. rend., 1851, 32: 60; Ann. (Liebig), 78: 225. 
«Oomp. rend., 1852, 34: 755; J. prakt. Chem., 56: 321. 

27 



28 ADULTERATED DRUGS AND CHEMICALS. 

for the i i i - - 1 time acetanilid and benzanilid, l>y the action of acetic 
anhydrid aod benzoic anhydrid, respectively, <>n anilin. This same 
worker bad made benzanilid seven years before by the interaction <>t' 
benzol 1 chlorid and anilin. 

In K,| .1. Fritzsche began to studj the action of nitric acid <>n 
phenol, His firel results were presented to the St. Petersburg 
Academj of Sciences November 6, 1867. 1 In thiw communication he 
reported the preparation of ortbo-nitrophenetol by the action of ethyl- 
io.ii.) on a silver sail of ortho-nitrophenol. The ester was extracted 
and purified by treating the mixture with ether, evaporating the sol- 
rent, and distilling the resulting reddish-yellow fluid. The product 
1 1 1 1 1 — obtained was nearly odorless, almost insoluble in water, but 
readilj soluble in alcohol and ether. Boiling caustic potash solution 
decomposed it w ith difficulty . 

The following year the same worker discovered and described 
isonitrophenic acid (para-nitrophenol) and some of it- derivatives. 
The derivative of particular interest in this connection is its ethyl 
. para nitrophenetol, prepared as was the ortho-nitrophenetol 
above. Para-nitrophenetol he described as a colorless crystalline body 
possessing an agreeable aromatic odor, nearly insoluble in water. 
soluble in ether and alcohol, and melting at ."'7 to 58 ( . 

Nothing of importance appeared again until A. Groll d announced 
the preparation of ortho-amidophenetol from ortho-nitrophenetol. 
The latter was prepare. 1 l>\ dissolving potassium nitrophenolate and 
ethyl bromid in from 8 to t part- of alcohol ami heating the mixture 
for a number of hour- in i sealed tube at from L40 to LdO C. 
Ortho-amidophenetol was made l>\ treating ortho-nitrophenetol with 
metallic tin and hydrochloric acid. From this time forward the nitro- 
phenetols were well known to organic chemists, being frequently 
employed l>\ them in their research work, and probably in the indus- 
trial world. Para-nitrophenetol was used by U. Schmitl and K. 
Mohlau in their investigation on azozy-azo- and hydrazo-phenetol, by 
Schmitt' during his studj of the constitution of the dichlorazophe- 
nols, and U. Mohlau in hi- dissertation very fully describes ortho- 
nitrophenetol. The latter, in his study of ortho-diamidodiphenetol,* 
full\ sets forth that the phenetols were common property. 

p rend., 1846, 20: 1081. 
31 Petereb. Boll, class.- phys. math., L868, 1ft: 161; .1. prakt Chem., 78:293; 
('hem. Centralb. (2), :{: 171. 

1. Clane phya math., 1869, 17:14.",; J. prakt. Chem., 76:267; 
Ann. (Iiebig), 110: 166; Jahreeb. (Liebigand Kopp), ll:4n7. 
*J. prakt Chem ,1876 - 12: 207. 
■ .1. prakt. Chen,.. 1-7- 2 . Iv 198. 
.'.I. prakt. Chen,.. 1879 (2), H»: 312. 

Dissertation, Freiburg, [879, i, b. 27, ft, through J. prakt Chem., 1880 (2), 21: 318. 
*J. prakt. Chen,.. 1879 2 . I!»: 38L 



PHENACETIN. 29 

By allowing 1 fuming nitric acid to act on phenetol, Cahours a obtained 
a solid and a liquid bod}-; the former he called dinitrophenetol and 
the latter mononitrophenetol. E. J. Hallock 6 repeated these experi- 
ments and obtained two similar bodies. He says: 

The solid, when purified by repeated recrystallizations, both from arid and from 
alcohol, was proved by an ultimate analysis to be a mononitrophenetol. Its melt- 
ing point, 58° G, and other physical properties coincide with that of para- 
mononitrophenetol, prepared by Fritzsche in 1858 by the action of iodid of ethyl 
upon the silver salt of para-nitrophenol. 

H. Andreae c in his excellent communication of nitro-ortho- and 
nitro-para-azophenetol shows that he was well acquainted with both 
the para- and the ortho-nitrophenetol. C. Willgerodt f/ gave a new 
method for preparing para-nitrophenetol, as indicated by the follow- 
ing equation: C 6 H 4 (N0 2 )Cl+C 2 H 5 OH=C 6 H 4 (N0 2 )OC 2 H 5 +HCl. H. 
Kolbe e gave additional methods for preparing these products. Other 
useful papers published bearing on these products were contributed 
by J. Berlinerblau/ C. Liebermann and St. Kostanecki, ^ and C. 
Willgerodt and M. Ferko. A 

The next step involved in the production of the phenacetins is the 
conversion of the nitrophenetols into the amidophenetols. This is 
usually done by the well-known nascent hydrogen process. 

Ortho-amidophenetol was first given to the world by A. Groll * in 
1875. The same compound was produced by M. Forster-?' in 1880 and 
by J. Berlinerblau^ in 1884. Meta-amidophenetol was well known to 
Berlinerblau,^ and Ph. Wagner, k and undoubtedly to other organic 
chemists in the early eighties. The discovery of para-amidophenetol 
is generally credited to the American chemist, E. J. Hallock, 6 but K. 
Schmitt's l work on the constitution of the dichlorazophenols shows 
that chemists were well acquainted with this compound before the pub- 
lication of Hallock's article. It was well known to Liebermann and 
Kostanecki? in 1884. 

The process described in the phenacetin patent for the manufacture 
of para-phenetidin was old and well known prior to the date when the 
patent was granted — 1889. Substantially the same method was 
described in 1884 by H. Kohler.™ 

a Ann. Chim. Phys.,-1849 (3), 27: 465. f/Ber. d. chem. Ges., 1884, 17: 876. 

6 Am. Chem. J., 1879, 1: 271. h J. prakt, Chem., 1886 (2), 33: 152. 

c J. prakt. Chem., 1880 (2), 21: 318. » J. prakt. Chem., 1875 (2), 12: 207. 

dBer. d. chem. Ges., 1881, 14: 2636; JJ. prakt. Chem., 1880 (2), 21: 341. 

ibid., 1882, 15: 1002. * J. prakt. Chem., 1885 (2), 32: 70. 

' J. prakt. Chem., 1883 (2), 27: 424; U. prakt. Chem., 1879 (2), 19: 312. 

ibid. (2), 28: 62. »'J. prakt. Chem., 1884 (2), 29: 257, 

/J. prakt. Chem., 1884 (2), 30: 97. 



30 \!>t I in: \ll l> DRUGS \NI» CHEMICALS. 

Meta-aeetphenetidin, or the roeta variety of phenacetin, was pre- 
pared by Ph. Wagner in 1886. This be accomplished by gently heat- 
ing together two parts of mefca-phenetidin and one part of acetic anhy- 
drid, cooling the resulting mixture, transferring the cooled crystalline 
mass t<» a funfTM. washing <»ut part of the impurities by means of 
water, and finally recrystallizing from 1 1 « > t water. The purified, glis- 
tening crystals were white, with a tint of red. melted at '.♦•;. 7 C. 
(uncorrected), and were difficultly soluble in water. 

After having prepared para-amidophenetol, Hallock* experimented 
further with this compound and reported one observation in the fol- 
lowing words: "This oil combines, like anilin, directly with acetyl 
chlorid to a crystalline solid.' 1 This crystalline solid, for the greater 
part, undoubtedly consisted of para-acetphenetidin, <>r phenacetin 
proper. Hallock, however, did not isolate the crystalline body and 
establish its physical properties and chemical composition. If he had 
done this it would have been a positive anticipation of the patent, 
and that pari <>f the patent alleging novelty or "a new pharmaceutical 
product' 1 would have hail it- mainstay undermined. All information 
about the crystalline !><>d\ was left vague and inconclusive by Hallock. 
who evidently did not think that it possessed any value or was worth 
further investigation. The statement that he obtained such a body 

b) tin- interaction of acetyl chlorid and para-amidophenetol was not 

useful to the public. 

The great desideratum with the medical profession has been a safe, 
effective, and inexpensive antipyretic. Theoldestand best febrifuge 
at this time (l sv,, i wa- quinine sulphate, but on account of it- costli- 
ness manj efforts had been made by chemists either to prepare quinine 
artificially or to find an efficient substitute. In L 842 Gerhardt* dis- 
tilled a mixture of quinine, water, and caustic potash and obtained a 
useful base which he called chinolin. It- high price from this source 
forbade it- use medicinally, hut by treating the alkaloid cinchonin in 
a similar manner he produced the same base. He was very much 
encouraged by the results of this investigation, for it was found that 
this comparatively cheap base and it- -alt- were active antipyretics. 
Chinolin tartrate wn- the earliest largely used artificial febrifuge. 
Chinolin itself was used a- a nucleus of many synthetic antipyretics 
or quinine substitutes. The successful preparation of synthetic qui- 
nine ha- been reported from time to time, hut at tin- writing ha- not 
been accomplished. Stimulated by the successof Gerhardt, K. Hlasi- 
wetzand L. Barth ' distilled resins in the same manner in which quinine 






• J. prakt Chem., -- 2 ::•_• 70. 

'-Am. Ch.-n... I.. 1879, 1: 271. 
Aim. (Liebig), 1842, 42: 310; J. prakt Chem., 28: 65. 

■MVi.-n. Aka.l. Ber., 1864, 49: L'Ctt; through Chem. Centralb., (2), 9:806. 



PHENACETIN. 31 

and cinchonin had been distilled and obtained a product which the}^ 
called resorcin. This chemical was at first extolled as an antipyretic 
also. 

From 1862 to 1879 there appeared to be a cessation of activities in 
the field of this class of remedies, but at the latter date W. Konigs a 
gave a new impetus to the work by his researches on chinolin, making 
it synthetically on a large scale from anilin. He was soon joined in 
his investigations by Baeyer, Skraup, Fischer, Knorr, Korner, and 
others, with very fruitful results. 

Doctors Fischer and Konigs in their studies on the alkaloids came to 
the conclusion that the properties of quinine did not reside in the 
quinolin nucleus, but in an oxygen or hydrogen-bearing element con- 
tained in or introduced into the nucleus. With this in mind their 
researches were prosecuted, and a number of new bodies were discov- 
ered, only two of which, however, appeared to be successful as 
medicinal agents. These were oxyhydromethylchinolin hydrochloride 
prepared by O. Fischer* and called '"Kairin,' 1 and tetrahydrometh^l- 
quinolin or tetrahydroethylquinolin, made by L. Hoffmann and W. 
Konigs c and named ^Kairolin. v The former was patented, highly 
extolled, and extensively advertised, and seems to have been the first 
medicinal chemical that was stimulated by the mercantile influence of 
letters patent. 

In 1881, L. Knorr d succeeded in preparing another very efficient 
antipyretic and named it antipyrin. It was well covered by patents. 
In France, however, a patent was granted on^ on a process for manu- 
facturing it as an anilin product, But antipyrin did not possess any 
industrial value and could not be sold as a patented remedy, for France, 
in the endeavor to hold the interests of suffering humanity above the 
interest of the individual inventor, does not grant patents on medicinal 
agents. The result was that antipyrin was not employed openty in 
France during the life of the patent, 

Acetanilid was discovered in 1852 by C. Gerhardt/ but its antipy- 
retic properties were not revealed until 1886, by G. Krieger.^ It is 
well known by its trade name Antifebrin. This compound unfortu- 
nately is prone to induce collapse when frequently administered in 
large doses. It was shown twenty years previous to this time by C. D. 
Schroff,^ A. Crum-Brown, and T. R, Fraser/' and more recently 

«Ber. d. chem. Ges., 1879, 12:453. 

&Ber. d. chem. Ges., 1883, 16:712; Arch. d. Pharm. (3), 21: 617. 
<Ber. d. chem. Ges., 1883, 16: 727. 

^Ber. d. chem. Ges., 1884, 17: 2032; J. Soc. Chem. Ind., 1885, 4: 59. 
e Comp. rend., 1852, 34: 755. 
/Centralb. f. Klin. Med., 1886, 7: 761. 
ff Wochenblatt d. K. K. Ges. Aerzte, Wien, 1866, 6: 157. 

h Trans. Royal Soc. Edin., 1867 to 1869, 25: 151 and 693 ; J. Anatomy and Physiol., 
(2), 8:478. 



32 AIM LTERATED DJJUG8 AND CHEMICALS. 

by Stolnikow, thai a modification of the chemical constitution of a 
chemical compound materially changes its physiological action. For 
example, the introduction of a methoxy group into morphine, convert- 
ing it into codeine, materially diminishes its narcotic action. 

Salol was prepared by M. Nencki 6 and investigated therapeutically 
l>\ Dr. Sahli.' This chemical was fully covered by patents. 

In L887 phenacetin, a- an antipyretic, first made its public appear- 
ance through communications by (i. Kobler d andE. Ghillany.' This 
chemical was prepared by Hinsberg. No unfavorable after symptoms 
were ooticed in 50 cases that were treated. C). Hinsberg and A. 
Kasl ' reported that para-acetphenetidin (phenacetin) in doses of 3 
grains acted like a strong poison, but in doses from 0.2 to 0.5 gram, 
exhibited t<> feverish persons, it was an effective antipyretic. 

I'.. Utescheri reported phenacetin as a very reliable antipyretic 
and singularly free from secondary effects. He described it as an 
odorless, tasteless, white (pinkish tint), crystalline body, having a 
melting point of L32.5 ( '. When heated with sulphuric acid, ethyl 
acetate i- produced. On heating a mixture of phenacetin, potassium 
hydroxid solution, and chloroform the isonitril odor is developed. 
Phenacetin heated with a potassium hydroxid solution li Iterates ethyl 
alcohol, which, on the addition of iodin, gives iodoform. This phenace- 
tin was manufactured l»\ V. Bayer & Co. 

'The above historical review quite fully sets forth the state of the 
ait and knowledge prior to the application for the phenacetin patent, 
June •_"'. i^>v. The various methods of making acetanilid and its 
physiological action were well known. Acetanilid produced unfavor- 
able after results when given in repeated large doses. Some undesir- 
able physiological actions had been removed or modified or mitigated 
by the introduction of certain well known groups. Phenacetin has 
the same chemical constitution as acetanilid. excepting that one of the 
atom- of hydrogen of acetanilid has been substituted by an ethoxy 
group. 

iZtschr. I'. Physiol. Cheni., 1884, 8: 235. 

'■ Polytech. NotiibL, Ism;. 41: L76; through Chem. Centralb., (3), 17: 751. 

Tli. -rap. Monateh. BerL, 1887, 1: :;:;::. 
rfZtachr. Osterr. Apoth. Ver., L887, 25: 323. 

Ztschr. Oeterr. Apoth. Ver., L887, 25: •';•';'■'; .1. Boc. Chem. Ind., 6:676. 

I entralb. Med. Wissensch., 1887, 25: 145. 
PApoth. Ztg., 1887, 2: 4o6; through J. Chem. Soc. Ind., 7: 227. 



PHENACETIN. 33 

PHENACETIN PATENTS AND TRADE-MARKS. 

United States Patent Office. 

Oskar Hinsberg, of Barmen, Assignor to the Farbenfabriken, Vormals Fr. Bayer & Co., of Elberfeld, 

Germany. 

PHENACETINE. 

Specification forming part of letters patent No. 400086, dated March 26, 1889. Applica- 
tion filed June 29, 1888. Serial No. 278593. {Specimens) 

To all whom it may concern : 

Be it known that I, Oskar Hinsberg, a citizen of the Empire of Germany, residing 
at Barmen, in the said Empire, have invented a Useful Improvement in the Manu- 
facture of a New Pharmaceutical Product, of which the following is a specification. 

My invention relates to the production of a new pharmaceutical product, a new 
antipyretic and antineuralgic, obtained by reducing nitrophenetole and melting the 
phenetidinchlorhydrate thus formed with dried sodium acetate and acetic acid. 

In carrying out my process practically I proceed as follows: Fifty kilos of the 
potassium salt of paranitrophenole are mixed with three hundred kilos of alcohol, 
adding forty kilos of bromaethyl. The mixture is heated in an autoclave at a pres- 
sure of three to four atmospheres during about eight hours. At this time the reac- 
tion is finishe 1, whereby paranitrophenetole is obtained according to the following 
equations: 

/ONa /OC 8 H s 

C s H 4 +C 2 H 5 Br=C 6 H t +BrNa 
\ NO \ N0 2 

In order to separate the mononitrophenole, which has not taken any part in the 
process, from the ether recently formed, the solution is treated with steam. By this 
operation the ether distills, leaving behind the paramononitrophenole. 

For the reduction of the paranitrophenetole forty kilos of this ether are mixed 
with sixty kilos of muriatic acid and sixty kilos of water. To this mixture are 
gradually added, at a temperature of 70° centigrade, twenty-five kilos of iron filings, 
the whole being stirred continually. As soon as the ether is entirely reduced, para- 
amidophenetole is obtained, as explained by the following equation: 

/OC 2 H 5 /OC 2 H 5 
C 6 H 4 +H 6 =C 6 H 4 +2H 2 
\ N0 2 \ NH 2 

The solution obtained in this manner is saturated with chalk diluted with water, 
and for the purification of the amido compound treated with steam the distillate is 
absorbed in water acidulated by muriatic acid. The muriatic salt of the para- 
amidophenetole crystallizes in white leaves. Fifty kilos of this product are melted 
with one molecule of melted acetate of sodium and twenty four kilos of glacial acetic 
acid. The melted mass is repeatedly boiled with water and the new monoacetyl- 
paramidophenetole obtained from the filterates after cooling. It has the following 
chemical formula: 

^-NH (C 2 H 3 0) 
Para C 6 H 4 =C 10 O 2 H 13 N 
\OC 2 H 5 

and is obtained according to the following equations: 

/NH 2 //NHC 2 H 3 

Para C e H 4 +CH 8 COOH=C,H 4 +H 8 0' 
\OC 2 H/ HPC 2 H 5 1 

13528— No. 80—04 3 



84 ADULTERATED DRUGS AND CHEMICALS. 

The monoacetylparamidophenetole crystallizes in white leaves, melting at L33° to 
136 centigrade. It is tasteless, little Bolublein cold water, more bo in hot water, 
l>ut easily in alcohol, chloroform, benzole, etc. It ie altogether different from the 
body described in the Year Book of Pharmacy \ 1883, page 1 u>, denominated "phe- 
naceteine". The formula of phenaceteine ie < ',„! I, < >. that of phenacetine C l0 I I, .< > 2 N, 
my produd containing nitrogen contrary t<> phenaceteine. The phenaceteine repre- 
aents a coloring matter, an armorphous carmine re.l powder, the acid solution of 
which i- yellow, the alkaline raspberry red, while my phenacetine is colorless, crys- 
tallizing in white leave.-, not changing color by addition of acids <»r alkalies. 

I la\ ing thus described my invention, what I claim as new . and desire to secure by 
•■ 

The produd herein described, which has the following characteristics: it crystal- 
lises in white leaves, melting a1 135 centigrade; nol coloring on addition of acids or 
alkalies; is little soluble in cold water, mure bo in hot water: easily soluble in alco- 
hol, ether, chloroform, r benzole; is without taste and has the general composition 
c H 0,N. 

( >. HlNSBBBO. 
Wit ip 

\\'m. Diestel, 
c. ,i. Heimpel. 

A pai. nt -hi phenacetin was granted t<> < >. Klimmek," of Chicago, 
111., under tin' chemical name oxyethylacetanilid. This patent was 
subsequently found t<> be ini alid. 

( >n reading the phenacetin patent (Hinsberg) it will bo observed 
tliai this patent is for the product ami the descriptive portion or speci- 
fication sets forth a process by which this product i-> made. In an 
attack "ii thr validity <>l' the patent tin- patentees took shelter behind 
this claim, alleging that the invention resided in the product ami not 
in the process. The patentee undoubtedly felt that there was nothing 
new in the process described, and it was :•. necessity to draft the patent 
in Buch a manner as to permit the al><»\e construction. There is noth- 
ing ii''\\ in tin' process. Everj Btep was well known to chemists long 
prior to the time of application lor the patent. The only useful im- 
provement in the process was its application on a commercial scale. 
and there could have been little hope of successfully defending such 

•a process in case of an attack. The claim for the product seems to be 

quite safe, for there i- nothing available in ordinary chemical litera- 
ture that conclusively anticipated the patent. The "crystalline solid" 
of Hallock, Bpoken of above, was undoubtedly impure phenacetin, but 

his information concerning the product was not sufficient anticipation, 
in the opinion of the courts, t<> invalidate a useful patent. 

The patent ha- been declared good and valid in law by the United 
Mat.- circuit court* for the eastern district of Pennsylvania, and the 
United States circuit court of appeals' for the third circuit affirmed 
the decision of the lower court. 0. Hinsberg must therefore at 
present he considered the acknowledged discoverer of phenacetin. 

«U. S. I-at. No. 806288, .June 28, 1898. 

b Dickenson et al. p. Mau.-r. Fed. Rept, 1901, 108: 233. 

'Mailer r. DickersOD et al., Fed. Kept., 1902, 113:870. 



PHENACETIN. 35 

Phenacetin is an eminently efficient medicinal remedy, and is conse- 
quently largely used in all parts of the civilized world. It is open 
to competition in every country except the United States. This situa- 
tion has caused the pharmaceutical profession of the United States 
to chafe considerabl} T for many years. The} r think such a discrimina- 
tion is an injustice. In many cases the burden became unbearable, 
and an illegitimate product began to be smuggled into this country 
from the Canadian borders. At present it is mostly brought in by 
unauthorized agents through the customs, duty paid, and delivered to 
the trade at about half the price charged by the holders of the patent. 
Much of this smuggled phenacetin bears the same label as the author- 
ized product, but it is expressly stated on the carton that "The resale 
and importation to the United States of America is prohibited." It 
is sometimes called "peddled" phenacetin. In some cases the dealers 
in these goods are not satisfied with their profits, but mix the phenac- 
etin with acetanilid and put it up in spurious packages closely resem- 
bling the original cartons. Adulterated phenacetin has caused the 
druggists of this country much trouble. 

For a time it was thought that phenacetin could be handled in this 
countiy under its chemical name, para-acetphenetidin, as were derma- 
tol (bismuth subgallate), antifebrin (acetanilid), and antipyrin (dime- 
thyloxjxhinizin), and as ari^tol (dithymol di-iodid) is at present; but 
the court held that the phenacetin patent covered this name a also. 
Whatever may be the status quo, it is quite evident that very little 
para-acetphenetidin as such finds its way into the United States 
except such as is brought in surreptitiously. 

The words "Phenacetin" and "Phenacetin -Bayer" are protected 
by United States registered trade-marks, numbers 18637 and 16392, 
respectively. If the usual custom should prevail, the owners of these 
trade-marks would have the exclusive right to use these words for 
thirty years from date of registration, but according to certain recent 
United States Supreme Court decisions 6 the word "Phenacetin" 
becomes public property at the expiration of the phenacetin patent; 
otherwise it would be necessary to use the chemical name or coin a 
suitable one for common use, as was the case with vaseline, known in 
the United States Pharmacopoeia, 1890, as petrolatum. The following 
interesting extract is taken from the Singer decision: 

Trade-mark — Doctrine as to Use op Name Given to Patented Article After 
Expiration of Patents. — It is the universal American, English, and French doctrine 
that where, during the life of a monopoly created by a patent, a name, whether it 
be arbitrary or be that of the inventor, has become by his consent, either express or 

a Dickerson v. Tinling, Fed. Kept., 1897, 84: 192. 

& Official Gazette, 1896, 75: 1703, Singer Manufacturing Company v. June Manufac- 
turing Company; Official Gazette, 1901, 97: 958, The HolzapfePs Composition Com- 
pany (Limited) v. The Eahtjen's American Composition Company. 



86 ADULTERATED DRUGS AND CHEMICALS. 

tacit, the identifying and generic name of the thing patented, this name passes to 
the public \\ itli the cessatioD of the monopoly which the patent created. 

Bams, bamb— Uss "i Name to Deceive. — Where another avails himself of this 
public dedication to make the machine and use the generic designation, he can do 
so in full forms, with the fullest liberty, by affixing such name t < » the machines, by 
referring to it in advertisements, and by any other means, Bubject, however, to the 
condition thai the name must l>e so used as no! to deprive others "t" their rights or to 
deceive the public, and, therefore, that the name must be accompanied with such 
identifications that the thing manufacture.! is the work of the one making it as will 
unmistakably inform the public of that fact 

On the principles embodied in the above decision the trade-marked 

name- Ant i|>\ iin. Castoria, and Lanolin have become public property. 
Any one is at liberty to manufacture the above articles, with the restric- 
tion that the public imi-i do! I"' deceived as to the maker. 

The underlying principle of our patent law- i- to stimulate and pro- 
tect invention. A- a patent covering a nevi product prevents the 
production of the article during its life by other processes, even those 
which 1 1 1 : i \ l>c more economical, the inventor of a new process for the 
preparation of a patented product will he prevented by the owner of 
the product patent from practicing hi- new process during the life of 
the patent. To this extent the patent laws may be said to temporarily 
discourage the invention of new and more economical processes for 
the production of such patented product-; hut if t<> remedy such diffi- 
cult) the protection by patent should he removed from this (dass of 
products these would be left unprotected as a class of useful inventions. 
It i- generally admitted that our patent laws do work hard-hips in a 
few cases like phenacetin, but if they were modified so as to remedy 
such difficulties much greater one- would become involved. Though 
inequalities exist, our patent law - a- a w hole are considered by those 
wh.. have made a studj <<( the Bubject to he the best in the world. 

The commission appointed by President McKinley to revise the 
United State- patent and trade-mark laws did not see it- way clear to 
make the change* desired by the American Pharmaceutical Associa- 
tion. For this the commission has been criticised harshly by the 
pharmaceutical pre--, which expresses Burprise that the recommenda- 
tion- of the association named were ignored. While the recommenda- 
tion- appear to be reasonable, it must be remembered that our patent 
law- are general, and of the large number of patents granted in the 
United States chemicals and medicinal remedies constitute only a 
small percentage. Such changes would involve special (class) legisla- 
tion for a comparatively few articles, which Congress is very much 
disinclined to enact, for experience ha.- shown that the results are 
frequently far from satisfactory. 



PHENACETIN. 37 

METHODS OF MANUFACTURE. 

The method described in the patent does not need to be considered 
further. The following equations serve to illustrate the successive 
steps and the principles involved in the manufacture of phenacetin : 

C 6 H 4 N0 2 OH + 6H = C 6 H 4 NH,OH + 2H 2 0. 
p-nitrophenol + nascent hydrogen = p-amidophenol + water. 

C 6 H 4 NH 2 OH + C 2 H 5 Br = C 6 H 4 NH 2 OC 2 H 5 + HBr. 

(p-aniidophenetol 1 
or >+ hydrobromic acid, 

p-phenetidin J 

C 6 H 4 NH 2 OC 2 H 5 + CH 3 COOH = C 6 H 4 NHC 2 H 3 OOC 2 H 5 + H 2 0. 
p-phenetidin + glacial acetic acid = phenacetin + water. 

Acetic anhydrid or acetyl chlorid can be used in place of glacial 
acetic acid. Phenacetin is obtained pure by recrystallization from 
hot water. In 1888 J. D. Riedel ffl took out a German patent for the 
manufacture of p-amidophenetol, which is the direct antecedent of 
phenacetin, by reducing 10 kg of diethyldioxyazobenzol with 6 kg of 
tin and 50 kg of 20 per cent hydrochloric acid. As soon as the diethyl- 
dioxyazobenzol is dissolved the mixture is rendered alkaline and sub- 
mitted to distillation. Para-amidophenetol is carried over with the 
aqueous distillate. The patentee states that this chemical is service- 
able in preparing phenacetin. The reaction is represented by the 
following equation: 

C 2 H 5 OC 6 H 4 NNC 6 H 4 OC 2 H 5 + 4H = 2C 2 H 5 OC 6 H 4 NH 2 . 

According to another method, 5 50 grams of chrysophenin, 100 grams 
of zinc dust, and 250 cc of hot water are mixed in a 2-liter flask and 
heated on a water bath with frequent agitation for one hour, then sub- 
mitted to distillation. The p-amidophenetol is removed from the dis- 
tillate by means of ether and the ethereal solution rendered acid with 
30 cc of dilute hydrochloric acid, which converts the phenetol into an 
ether insoluble hydrochlorid. The ether is drawn off and the aqueous 
solution concentrate to crystallization. 

H. N. Morse c in 1878 treated p-amidophenol with acetic acid with 
the expectation of getting an acetic acid salt of p-amidophenol, but 
obtained p-acetylamidophenol. In 1891 E. Taiiber^ secured letters 
patent in Germany for a process that converts this chemical into phe- 
nacetin. The method is as follows: Mix 150 grams of p-acetamido- 
phenol, 165 grams of potassium ethyl sulphate, 40 grams of sodium 
hydrate (dissolved in 500 cc of 60 per cent alcohol) in an autoclave 

a D. E. Patent No. 48543, Dec. 28, 1888. 

6 Bender und Erdmann, Organische Praparate, 1894, 2: 466. 

cBer. d. chem. Ges., 1878, 11: 232. 

dj). P. Patent No. 85988, June 19, 1894. 



ADULTERATED DBUGS AND CHEMICAL-. 

and heat the mixture for four hours al L50 C. On diluting the result- 
ing solution with three parts of water the phenacetin separates out in 
fairly pure crystals. This appears to be the method now used in the 
manufacture of phenacetin. 

The chemical constitution of phenacetin can readily be made out 
fn.ni what has been said above. Its chemical name-, are p-acetamino- 
phenol ethyl ether, p-acetphenetidin, p-acetamidophenetol, etheocy- 
acetanilid, andoxyethylacetanilid. The last two names show their close 
relation to acetanilid. This is also Bhown by the following formulae: 

< MIC II < i 
phenacetin |. 
» 1 1 

These two compounds resemble each other not only in chemical 
constitution, but also in their physical properties. 

PHYSICAL AND CHEMICAL TESTS. 

THE Mil l I n«. POINT. 

Many and varied ha\ e hern the tests proposed for establishing the 
pmity of phenacetin, but at present themost reliable is its melting 
point, which is near L36 C. This important constant is disturbed by 
the presence of any impurity. Bnch as unconverted p-phenetidin, ace- 
tanilid, antipyrin, salicylic acid, quinine sulphate, starch, milk sugar, 
etc. All powders so far examined in this laboratory having a melting 
point within l \ normal have deported themselves in every 

c( like pure phenacetin. 

The presence of unconverted p-phenetidin " in phenacetin isdetected 
h\ melting 2.5 grams of pure crystal chloral hydrate in a test tube on 
I water bath, then adding 0.5 gram of phenacetin, and continuing the 
heating fora short time. If the phenacetin is pure, only a pinkish 
color del elope on prolonged heating, whereas the presence of p-phene- 
tidin (p-amido-phenetol) gives within five minute- an intensely red or 
reddish-violel coloration. * 

The one adulterant <>f phenacetin which appears to be difficult of 
detection is acetanilid. It- influence <>n the melting pointof phenace- 
tin was noted by E, Utescher, 6 who found that phenacetin mixed with 
: cent of acetanilid -how-, at from 113° to 114 C, minute drops 
of liquid on the Bides of the capillary tube and melts completely at 
from L27 to 128 C. EL Schweitzer e studied the melting points of 
various mixture- of phenacetin ami acetanilid and observed the strange 
phenomenon that all mixtures of these two chemicals began to melt at 
92 C. Neither phenacetin nor acetanilid -how- the least change at 

"I'hann. Ztg., 1891, 86: 185, through J. ^„: Ohem. bid., 10: 799. 
&Apoth. Ztg., 1888, 8:483, through Ztachr. anal. Chem., 27:666. 
5 . Chem. End., 1896, 1 I 



PHENACETIN. 



39 



this temperature. Schweitzer thinks this test is positive in identify- 
ing mixtures of these chemicals and that further examination is useless. 
The following table is taken from his communication: 

Melting points of mixtures of phenacetin and acetanilid (Schweitzer). 





Mixture consisting 






No. 


of— 




Completely 
transpar- 
ent at— 


Phenace- 


Acetani- 


melt at — 




tin. 


lid. 








Per cent. 


Per cent. 


°C. 


°c. 


1 


99 


1 


92 


134 


« 


95 


5 


92 


133 


3 


85 


15 


92 


128 


4 


66| 


33^ 


92 


126 


5 


60 


40 


92 


125 


6 


50 


50 


92 


122 


7 


40 


60 


92 


118 


8 


33£ 


66| 


92 


114 


9 


15 


85 


92 


110 


10 


5 


95 


92 


106 


11 


100 





133 


134.5 


12 





100 


112 


114 



Examinations made in this laboratory of mixtures of phenacetin and 
acetanilid gave the following results: 

Melting points of mixtures of phenacetin and acetanilid (drug laboratory). 



No. 


Percentages in 
mixture of— 


Melting point. 


Phenace- 
tin. 


Acetani- 
lid. 


Begins to 
melt at— 


Completely 
transpar- 
ent at — 


1 

3 

4 
5 
6 

7 


Per cent. 
90 
75 
50 
25 
10 
100 



Per cent. 
10 
25 
50 
75 
90 

100 


°C. 
96 

90 

90 

95 

133.5 
112 


°C. 

127 
121 

92 

99 

no 

134.8 
113.8 



The above observations were made several times on finely powdered 
anhydrous thoroughly mixed material with a standard thermometer, 
the entire mercurial column being in the heating medium. The melt- 
ing points were taken in a long capillary tube attached to the thermom- 
eter, and both were placed in a test tube 20 cm long and 2 cm in diame- 
ter. The test tube was then filled with glycerin and placed in a liter 
Erlenmeyer flask nearty filled with glycerin. The temperature was 
gradually raised and kept uniform throughout the mass by a continual 
current of air. The results are not in perfect accord with Schweitzer's. 
The various mixtures began to soften at about 92° C, but not uni- 
formly at that temperature. 



40 



Aiui.i EB \ 1 i: 1 > DRUGS \ N I ► ( HEM1CALS. 



Since these determinations were made an article by G. M. Bering 
has appeared, from which tin- following table on the melting points of 
mixtures of acetanilid and phenacetin is taken: 

i' mi riuri .»• uf act tanilid and /<//< nac* I 



A.'.tani 
lid. 


Khrlnka 






plete 


1 




1 




' 


1 


126 










II.-. 


126 








110 


L24 




LSI 


1 


106 


L20 


L25 L26 


L8Q 




LOO 


106 


1U 111 


124 


10 


too 


105 


L10-112 


L20 


IS 




L06 


L10-112 


L20 




92 


LOO 


L06 L06 


L18 






'.•l 




116 










n:» 




S 




92 '.'I 


LOG 


40 


M 


90 




L06 










100 


;..i 


BO 








56 


77 








60 


B2 


38 




'.M 


65 


B2 


-7 




'.M 


7(i 


-7 


90 






76 


B8 






96 


BO 


B8 






99 


86 


90 






105 


90 


92 




100-101 


108 


96 


96 


L02 


L07-108 


111 



These results do not add anything to what baa already been noted, 
l>ut they do show clearly, first, that chemists have not yet thoroughly 
Learned how to determine the point at which a substance melts or 
begins to soften; and, second, that all mixtures of phenacetih and 
acetanilid do not begin to soften uniformly at 92 0. 

SOLUBILITY. 

The solubility of phenacetin Is of service in detecting such adul- 
terant- as sodium bicarbonate, sugar, starch, quinine sulphate, and 
antipyrin. 

CHEMICAL TESTS FOB ACETANILID IN PHENACETIN. 

Numerous chemical tests have been proposed to detect the presence 
of acetanilid in phenacetin, but so far the ideal method has not been 
found. These two chemical bodies bear such a close resemblance to 
each other that it is difficult to detect the cheaper acetanilid in the 
more expensive phenacetin. The reverse is quite easy to accomplish. 
The following tests are given in the order of their usefulness. 

BROMIM Tl -I 1 ■'.. I I [B84 HSOB N 

Boil 0.1 gram of the suspected mixture with L0 cc of water for 
several minutes, cool, filter, and to the filtrate add bromin water until 
a 3 ellovi coloration is produced. With phenacetin no turbidity results, 

a Drag. Circular, 1903, 17: L84. 

'-PI. am,. Ztechr. t. Etass., L888, 27: 794. 



PHENACETIN. 4 1 

but the presence of acetanilid causes a precipitate of p-bromacetanilid 
which melts at from 166 to 168° C. This test is recognized in the 
British and German pharmacopoeias. 

Saponification Test (P. X. Raikow and P. Schtarhaxow).« 

This test is based on the fact that acetanilid decomposes more readily 
with a fixed alkaline solution than phenacetin. It is applied as follows: 

In a test tube of suitable size, provided with a perforated rubber 
stopple carrying a bent tube about 20 cm long, place 1 gram of 
acetanilid or phenacetin or a mixture of the two and 8 cc of a 25 per 
cent solution of potassium h} T droxid and submit the mixture to distil- 
lation. Receive the distillate in a second test tube containing about 
5 cc of a good bleaching-powder solution. With acetanilid alone a 
violet blue or purplish coloration develops, due to the anilin distilled; 
with phenacetin a brick-red opalescent solution forms b}^ the inter- 
action of the phenetidin and calcium hyperchlorite; with a mixture 
of phenacetin and acetanilid the first few drops of the distillate give 
the violet-blue coloration, w^hile the latter portion of the distillate, 
received in a separate test tube, gives a brick-red turbidity and some 
coloration. With a considerable quantity of phenacetin the color 
becomes intensely red and the turbidity increases. In order to clearly 
differentiate between these two colorations it is necessary to collect 
the first few drops of the distillate for the acetanilid test and the latter 
portion for the phenacetin test. If this precaution is not carefully 
observed the phenetidin color reaction will obscure the anilin test, and 
the results are valueless. If acetanilid is not present the first few 
drops of the distillate will not produce any coloration with the calcium 
hyperchlorite solution. 

G. M. Beringer 6 has studied this method very thoroughly and sug- 
gests several changes which he thinks materially improve it. By 
replacing the chlorinated-lime solution with a chlorinated-soda solu- 
tion the end color reactions obtained become much more character- 
istic. With this reagent, acetanilid gives a decidedl} T purple tint not 
in the least obscured by a cloudy brownish-red, as is the case with the 
chlorinated-lime solution. With phenacetin the sodium -hyperchlorite 
solution changes to a "bright orange" (brick-red) and remains clear. 
The chlorinated-soda solution is considered to be a far more delicate 
and satisfactory reagent. Beringer sa.ys that he did not have any 
difficulty in detecting 3 per cent of acetanilid in phenacetin. 

Another modification of this test suggested by the same writer is to 
heat together for one minute 0.1 gram of the substance and 3 cc of a 
sodium-hydroxid solution, cool thoroughly, add 5 cc of a chlorinated- 
soda solution, shake well, and set aside for a few minutes. If phenac- 
etin only is present the upper layer is never of a deeper tint than 

"Oesterr. Chem. Ztg., 1900, 3: 125. ^Drug Circular, 1903, 47: 184. 



42 ADULTERATED DRUGS AND CHEMICALS. 

yellow, 1 >nt the presence of acetanilid imparts to it a purplish-red 
shade. 

Other modifications are given, but tin- following is considered the 
most delicate: Intimately mix 1 gram of sodium peroxid with 0.1 gram 
of tlif substance t<> be tested, place the mixture in a 15 cm test tube, 
and add .". <•<• <>t' water. After the vigorous action ceases, shake thor- 
oughly, cool, and add 5 cc of sodium-hyperchlorite solution, again shake 
\ igorously, and set aside. If the phenacetin is pure the liquid remains 
colorless, or, at most, after long standing assumes a pale-yellow color, 
while the presence of acetanilid gives a purplish-red tint shading to 
pink, depending u] the amount of the adulterant present. 

Judging from the chemical composition of phenacetin and acetan- 
ilid and the final cold- reactions, it i-. quite probable that the sodium 
peroxid act- mainrj as a saponifying agent, as dor- potassium 
bydroxid in the original method. 

MmtccBore Nnmn: Tbrt (P. C. Plttggi 

Boil together 0.5 gram of phenacetin and 8 cc of water, cool and 
filter. To the filtrate add a fragment of potassium nitrite and 0.5 ec 
of dilute nitric acid and boil the mixture a few minute-. Then add 
1 ec of raercuroufl nitrate solution containing nitrous acid, boil again, 
and if a red color develops acetanilid is indicated. 

[ODOPHXNOL Tl>l.'< 

This test was adopted by the German Pharmacopoeia] Commission 
for the identification of acetanilid, and is recognized by the fourth 
edition of the German Pharmacopoeia, hut the reaction has been proved 
to he worthless. Phenacetin responds affirmatively to this test, which 
i- executed a- follow -: 

Heat together for a few minutes 0.2 gram of acetanilid and *j <•<■ of 
25 per cent hydrochloric acid. A. clear solution results, which, with 
1 n- of a .'. per cent solution of carbolic acid and a suitable amount of 
a good calcium hypochlorite solution (1 in 10) gives a dirty violet-blue 
color. On rendering this solution alkaline with ammonia water an 
indigo blue develops. The test has been modified in various ways, 
but so far the results are not satisfactory. 

[somxkil Reaction. 

This test was originally proposed by A. W. Hofmann* as character- 
istic of anilin. It has, however, been found that primary amines in 
genera] respond to this reaction. It is therefore a group reaction and 
can not with safety be employed to detect one compound containing 

Lrch. d. Pharm., 1800, 228: 9; J. Anal. Appl. Chem., 7: 77. 
& Arch. -1. Pharm., 1887, 225: 1042. 
<-Ber. d. chem. Gee., 1870, 3: 7G7. 



PHENACETIN. 43 

an amido group in the presence of another compound containing- the 
same group, even though one is more readity acted on b} r the agents 
employed than the other. The test is applied b} T heating together for 
a few minutes about 0.5 gram of the substance and 5 cc of a 10 per 
cent solution of sodium hydroxid, then cautiously adding a few drops 
of chloroform and setting the mixture aside for a few minutes. If a 
primary amine is present the characteristic offensive odor of phenjd- 
carbamine can readily be detected. This reaction has received official 
sanction in the pharmacopoeias of the United States, England, and 
Germany, and is so frequently cited as suitable for detecting acetan- 
ilid in phenacetin that a short resume of some of the misleading state- 
ments made concerning it is desirable. 

CONFLICTING STATEMENTS REGARDING THE ISONITRIL REACTION. 

As early as 1887 Utescher a found that after heating phenacetin, 
sulphuric acid, and alcohol together, rendering the mixture distinctly 
alkaline with a fixed alkali, and adding a few drops of chloroform, the 
repugnant odor of carbylamine was developed. The sulphuric acid 
probably decomposes the phenacetin into acetic acid and phenetidin 
(C 6 H t NH 2 OC 2 H 5 ). 6 Schwartz states that a simple method for deter- 
mining acetanilid in phenacetin is b}^ means of the isonitril reaction. 
W. Lenz/ in his review of special analytical methods, says that it is 
self-evident that for the detection of acetanilid in phenacetin the well- 
known "isonitril reaction" can be employed. Again, this author 
states that a mixture of acetanilid and phenacetin will give the "isoni- 
tril reaction." C. Piatt e says: 

Another test useful also in detecting small quantities of acetanilid in the presence 
of phenacetin is to treat the mixture with caustic soda or potash in the presence of 
chloroform, when, if acetanilid be present, the characteristic odor of isonitril is 
given off. If phenacetin be heated with alcohol and sulphuric acid the character- 
istic odor of ethyl acetate is observed; by heating the solution thus formed with 
caustic potash and chloroform, the carbylamine reaction is obtained. 

In an article entitled "Adulteration and Substitution of Drugs," by 
Schweitzer/ the following statements are found: 

Acetanilid is identified * * * by heating 0. 10 gram of the powder with 1 cc of 
NaOH (15 per cent NaOH) and three drops of chloroform, whereupon the offensive 
smell of phenyl-isocyanide is given off. * * * For the identification of the mix- 
ture (acetanilid and phenacetin) it is sufficient to state that the substance begins to 
melt at 92° C. and becomes completely transparent below 134° C. On heating 0.10 
gram of powder with 1 cc of caustic soda (15 per cent NaOH) and 3 drops of chloro- 
form the offensive smell of phenyl-isocyanide is observed. 

aApoth. Ztg., 1887, 2: 436, through J. Soc. Chem. Ind., 7: 227. 

&Ann. (Liebig), 1899, 309: 233. 

cPharm. Ztg., 1888, 33: 357. 

tfZtschr. anal. Chem., 27: 665. 

« J. Anal. Appl. Chem., 1893, 7: 77. 

fj. Soc. Chem. Ind., 1895, 14: 852. 



44 ADULTERATED DRUGS and UHEMICAL8. 

According bo G. Guasti' phenacetiD gives the phenyl-carbylamin 
reaction. V. S. Hyde*say9: "Contrary to some writers, phenacetin 
will give the isonitrile test, and bence can not be distinguished from 
acetanilid by this reaction." V. X. Moerk' obtained this reaction in tin- 
usual way with both acetanilid and phenacetin, but Bays that 1 per 
cent of 'In- former Is readily detected in the latter when a solution of 
potassium permanganate is added to destroy odors that arc formed 
l»\ other bodies and which interfere with the test. P. W. Squi 
reports satisfactory results with this modification. 

The Isonitril reaction is recognized as an identifying tesl for aceta- 
nilid by the present British, German, and United States pharmaco- 
poeias. Neither of the two former pharmacopoeias mentions this test 
in connection with phenacetin, and the latter does not recognize this 
chemical. Such careful workers as Helbing, Fischer, and Fluckiger 

State that phenacetin gives the isonitril reaction. 

From this array of contradictory statements it is not surprising that 
a worker not thoroughly familiar with the literature of this subject 
should make the error of basing bis conclusions on this reaction. 
These discrepancies are undoubtedly due to the fact that phenacetin is 
less readily decomposed with a fixed alkali solution than is acetanilid. 
The conditions under which the te^t has been applied by the various 
workers have not been uniform, and indeed it would be difficult to 
prescribe proper limitations, as has been discovered in the drug labo- 
ratory. The test has proved itself to be unreliable for the purpose of 
detecting acetanilid in phenacetin. 

COMMERCIAL SAMPLES. 
FAMOUS LABELS. 

Original L-ounce packages of the authorized phenacetin were pur- 
chased in Washington, D. C, while the unauthorized product and 
p-acetphenetidin were secured in Philadelphia, Pa. This is not 
intended to imply that the druggists of Philadelphia were trafficking 

in the forbidden phenacetin while those in Washington were not. 

All samples of the regular article were marked as follows: 

Trade-marked name: Phenacetin. Registered trade-mark,] Ounce Phenacetin- 
Bayer. Patented March 26, 1889, CJ. S. Patenl Xr. 400066. Manufactured by Far- 
benfabriken, vorm. Frieda Bayer and Co., Elberfeld, Germany, for United States 
patentee. This package ia Bold to the ownerofU. B. Patent Xr. 400086 March &6, 
L889, the Farbenfabriken of Elberfeld Co., 40 stone Btr., New York City. 

-. Lmi, L894, 4: 96, through J. Boc Chem. Ind., 14: 77. 
&J. Amcr. Chem. Boc., 1896, 17: 933. 

Am. J. Pharm., L896, «',s - 
d Squire's Companion Brit Pharm., 1899, I7thed., p. •>. 



PHENACETIN. 



45 



A genera] registered trade-mark, No. 31422, consisting of the figure 
of a winged lion resting one forepaw on a globe while the other paw 
grasps a caduceus, is also found on each package. 

The cartons of the irregular product are plainly marked as to the 
manufacturer and source of production. Each package is labeled in 
English, French, and German as follows: 

"Patented in the United States of America, Nr. 400086. Phenace- 
tine-Bayer. The resale and importation to the United States of America 
are prohibited." 

The sample purchased by its chemical name bore the following 
label: 

"1 lb. Paracetphenetidine Powder B. P. This serves to remind that 
this article must not be sold to the United States, it being patented in 
that country. Made in Germany. E. Merck. Darmstadt.'' 



ANALYTICAL RESULTS. 

The tests applied to these samples were such as have been found 
of service in establishing the quality of phenacetin, and include phys- 
ical appearance, melting point, solubility, and the presence of 
p-phenetidin. 

Analyses of commercial samples of phenacetin. 



Number 
on pack- 
age. 



Kind. 



Physical appearance. 



Melting 


Solu- 


point. 


bility. 


°C. 




134.8 


Normal . 


135.0 


....do... 


135.0 


...-do--- 


134.9 


...-do... 


134.6 


-...do-.- 


135.0 


....do... 


134.4 


....do... 


134.6 


....do... 


a 122-123 


....do... 



P-phenetidin. 



1726 
1743 

1782 
04082 
155641 
339232 
339243 
339255 
845388 



Authorized Micaceous scales 

— do do 

do do 

Paracetphenidin ..! Micaceous scales (powdered) 

Unauthorized j Micaceous scales 

Authorized ' do 

do do 

— do do 

Unauthorized ■ Micaceous scales (some large) 



None. 
Do. 
Do. 
Do. 
Do. 
Do. 
Do. 
Do. 
Do. 



"Began to soften at 94° C. 

All of these samples are of satisfactory quality except No. 845388, 
which is a mixture of phenacetin and acetanilid, containing about 20 
per cent of the latter. This sample and the paracetphenidin were 
purchased at -the same place, while the other unauthorized sample 
was obtained from a different source of supply. On examining the 
carton containing the mixture of phenacetin and acetanilid it appeared 
to be spurious. The two empty cartons containing the unauthorized 
phenacetin were sent to the patentee's agent in New York with the 
request that he express an opinion as to their genuineness. These 
packages were immediately returned, No. 845388 being marked coun- 
terfeit, the other genuine. The bogus carton resembled the genuine 
one very closely, though there was a difference in color, style of type, 
and the ornamental lines employed. 



4t'» ADULTERATED DBUGfl AND CHEMICALS. 

COMMERCE IN PHENACETIN. 

United States letters patent grant to an inventor "the exclusive 

right to make, use, and vend" his "invention throughout the [Jnited 

States and the Territories thereof." This clause effectively restricts 

to the inventor, bis heirs, <>r assignees, the right to import his pat- 

product into the United States when manufactured abroad. 

rding to certain decisions it i- held by Home that if the article 

i- purchased from the patentees, tribute has 1 n paid to the monopoly 

and the right is therefore acquired to import, use, and sell the article, 
bought elsevi here, \\ ithin the United States. This privilege, however, 

not <»lit:iin \\ ben purchases are made from others than the owners 
of the patent, because thej have n<>t then received any remuneration 
for the article bo purchased.' U these principles governed the phe- 
nacetin trade the present Btrained situation would Dot exist. 

Another factor which has assumed considerable proportions in the 
commercial world must l>«- considered. The patentee has the right 
and power to Bell hi- product subject to the express conditions that it 
inu-t not In- imported into tin- United States or -old here. 1 1 « » has the 
same vested right to sell the product with restrictions and limitations 
that In' ha- to sell it at all. It i- a matter of record that the patentees 
of phenacetin expressrj -tat.' on every package -old in foreign coun- 
tries that it- importation into the United States and resale there Is 
prohibited. Manufacturers of p-acetphenetidin specify on every 
package that it must not be Bold in the United States. The following 
extracts from the decisions of tin- United States circuit court of 
appeals express tin' rulings on this point in a very succinct manner: 

l. One purchasing in :i foreign country an article protected by a [Jnited 31 
patent, from persons other than the owner of tin- [Jnited States patent or hisven- 
iii ii"t ii t n m .rt ami sell tin- same in tlii- country without infringing tin- United 
itent 
'•in- purchasing hi uitry, from the owner of the [Jnited states pat- 

ent, patented goods having marked upon them a condition that they should not be 
imported into the Unit) . not import and Bell them here without being 

guilty of infringement. 

Judging from past reports and recent developments, our excise laws 
have been grossly violated by the smuggling of phenacetin, which is 
clandestinely brought into tin- country in violation of out- customs 
law-, or i> regularly imported, duty paid, and secretly -old to con- 
sumers. Pharmaceutical journals recount the arrests of numerous 
vendor- of this illicit product. These smugglers have been appre- 
hended in every section of the Union, and many litigations have been 
instituted, numerous injunction- issued, and tine- imposed. 

ted in Dickeraon v. Tinling, Fed. Kept., 1888, 84: 192. 
' Dickeraon p. Tinling, Fed. Kept, 1888, s4: 192. 
cDickereon >. Tinling, Fed. Kept, 1887, s-l: 192. 



PHENACETIN. 47 

The collector of customs of the port of New York seized and con- 
fiscated illegally imported phenacetin, advertised it for sale in the 
customary manner, and sold it at public auction in that cit} r in 1898. 
The purchaser at the time of the sale knew that the goods were 
smuggled, and infringed the patent. Before he could resell his pur- 
chase the representative of the patentees served an injunction pre- 
venting such sale. The case was taken into the United States circuit 
court, and the defendant enjoined from directly or indirectly using or 
selling the patented drug phenacetin. An appeal was taken to the 
United States circuit court of appeals, and this court affirmed the order 
of the lower court, a The defendant claimed, first, that the passage of 
the phenacetin through the hands of the Federal Government in 
some way abrogated the rights of the patentee; and, second, that by 
the condemnation proceedings and statutory notice the title of the 
property passed to the purchaser without incumbrance or reservation. 

In view of the decision given above, it seems that these contentions 
do not obtain in the case of patented articles of the phenacetin type. 
The decision further states that the patentee "has no title to or lien on, 
or legal or equitable interest in the infringing property." The pur- 
chaser filed an application for a refund of the buying price, but the 
Treasury Department reported that it could not comply with this 
request, b as the law does not provide for refunds under any circum- 
stances. The defendant refused to comply with the order to surrender 
the goods purchased from the Government, This curious legal 
entanglement as to the disposition of smuggled patented drugs is at 
present receiving the consideration of the Attorney-General. The issue 
is of the greatest importance, and has attracted the attention not only 
of the Treasury officials, but of the Patent Office authorities as well. 

«Dickerson v. Sheldon, Fed. Rept,, 1900, 98: 621. 
6 Oil, Paint, and Drug Reporter, August, 1903, 64: 24. 



O 






I k TJ7 




mm 



